MRCPass Notes

BY Dr. Ahmed Hakim

Compiled by aHMED hakem ahmedhakim_227@yahoo.com http://ahmedhakim.125mb.com

Stimulation of receptors leads to: Vasoconstriction decrease in gut motility uterus contraction decrease in pancreatic exocrine secretion Cholera toxin: activates G protein, which activates adenylate cyclase. Elevated cAMP results in unrestricted chloride secretion from villous crypts. Iron is absorbed in upper small intestine. Iron absorption is increased with ascorbic acid. The sulfate form contains more elemental iron per dosage unit than gluconate. The list of autosomal dominant disorders are: achondroplasia antithrombin III deficiency C1 esterase inhibitor deficiency Ehlers-Danlos syndrome Familial hypercholesterolaemia Gilbert's disease hereditary haemorrhagic telangiectasia hereditary elliptocysis, hereditary spherocytosis Huntington's disease idiopathic hypoparathyroidism intestinal polyposis marble bone disease Marfan's syndrome neurofibromatosis Peutz Jeghers syndrome polycystic kidney disease (adult) protein C deficiency osteogenesis imperfecta Treacher Collins syndrome tuberous sclerosis Von Willebrand's disease The list of autosomal recessive conditions are: oculocutaneous albinism alkaptonuria Bartter's syndrome cystic fibrosis endemic goitrous cretinism

galactosaemia Gaucher's disease glycogen storage disease homocystinuria phenylkeonuriat Sickle cell disease Wilson's disease xeroderma pigmentosa The features of X linked inheritance are: Males are all affected Females only occasionally show mild signs of disease Each son of a carrier a 1:2 chance of being affected Each daughter of a carrier has a 1:2 risk of being a carrier Daughters of affected males will all be carriers Sons of affected males will be affected X linked dominant (rare) X linked Hypophosphataemic rickets von Willebrand's disease X linked recessive Beckers muscular dystrophy Duchennes muscular dystrophy Fabrys disease Hunters syndrome Glucose 6 Phosphate denydrogenase deficiency red-green colour blindness haemophilia A and B Testicular feminisation syndrome Wiskott Aldrich syndrome Mitochondrial DNA is inherited from the mother. Mitochondrial DNA codes for proteins in the oxidative phosphorylation / electron transport chain. Leber's optic atrophy is a form of mitochondrial disease. DNA Bases are paired with hydrogen bonds but the ribose-phosphate complexes are paired with covalent bonds. Histones allow DNA to twirl round it to form stable nucleoprotein complexes. Coding sequences (exons) are interspersed with introns. In RNA, uracil represents the thymine residues in DNA. mRNA translation into proteins occur in the cytoplasm. RNA polymerase II transcribes mRNA Transfer RNA (tRNA) is a small RNA chain (74-93 nucleotides) that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein

synthesis during translation. It has sites for amino-acid attachment and codon (a particular sequence of 3 bases) recognition. The codon recognition is different for each tRNA and is determined by the anticodon region, which contains the complementary bases to the ones encountered on the mRNA. Each tRNA molecule binds only one type of amino acid, but because the genetic code is degenerate, more than one codon exists for each amino acid. Both coding (exons) and non coding regions (introns) exist on RNA. Reverse transcription involves transcription of RNA to DNA (used by retroviruses). Only about 5% of DNA codes for proteins. Multiple codons (triplets of nucleotides) code for the same amino acid. Antisense oligonucleotides are sequences of DNA which are complementary to RNA. They bind to RNA and stops it from processsing. PCR In PCR, two primers are required for a start and stop sequence to amplify the DNA strand. DNA polymerase needs to be stable at high temperatures and hence thermostable enzyme from T. aquaticus is used. The mixture is heated to below 100C. DNA polymerase causes synthesis of DNA between two primers Reverse transcriptase PCR is used to amplify RNA, whilst conventional PCR is used to amplify DNA Restriction enzymes cut DNA at nucleotide sequences specific to each restriction enzyme. HindIII and EcoRI are examples of restriction enzymes DNA ligase and polymerase are involved in joining and linking DNA together. Plasmids are circular molecules of bacterial DNA separate from the bacterial chromosome. They are usually small, consisting of a few thousand base pairs. They carry one of a few genes and have a single origin of replication. A Barr body is an inactivated X chromosome. The human karyotype consists of 22 pairs of autosomes and 1 pair of sex chromosomes totalling 23 pairs altogether. Heterochromatin contains mostly inactivated genes. Telomeres are distal extremities of chromosomal arms but centromeres provide a point of attachment for the mitotic spindle. Northern blotting detects RNA Southern blotting detects DNA. Western blotting can be used to detect and quantify proteins

The karyotype 46 XX, t (4;8)(q26;p21.3) describes a female with a normal number of chromosomes but a translocation between the long arm of chromosome 4 (q) and the short arm of chromosome 8 (p). Genomic imprinting refers to the difference in phenotypic presentation depending on the origin of the disease chromosome from either maternal or paternal. Conditions with genomic imprinting: myotonic dystrophy Beckwith-Wiedemann syndrome Prader Willi syndrome Angelman syndrome Anticipation refers to increase in the number of trinucleotide repeats The list of trinucleotide repeat disorders are: Fragile X Huntington's chorea Myotonic dystrophy Friedreich's ataxia Spinocerebellar ataxia Spinobulbar muscular atrophy Diseases which have mitochondrial inheritance (passed on by the mother): Kearn Sayre's MELAS MERRF progressive external opthalmoplegia Leber's optic atrophy There are cyclins at various phases of the cell cycle (G1 to S phases) which can bind to enzymes such as threonine and serine kinases (also known as cyclin dependent kinases). These regulate the progression of the cell cycle. Eukaryotes (higher organisms) have muliple chromosomes in a genome which is separated from the rest of the cell by a nuclear membranes. Prokaryotes lack a membrane bound nucleus, their DNA occurs in a circular form. Oncogenes Proto-oncogenes and oncogenes encode growth factors. A single aa mutation is enough to change the proto-oncogene into an oncogene. Mutated proto-oncogenes that cause cancer are called oncogenes. Examples of oncogenes are: Ras oncogene is involved in sporadic tumours (colon and lung) and rhabdomyosarcomas. c-myc translocation occurs in Burkitt's lymphoma.

N-myc proto-oncogene is seen in neuroblastoma. SRC oncogene is associated with sarcoma. *Ras is the commonest oncogene (others include myc, fos and jun) Fas ligands and caspases trigger apoptosis. Bax, Bad and Bak are members of the oncogenes which promote cell death. Bcl-2 inhibits apoptosis. Bcl-2 prevents cell death by blocking apoptosis, preventing p53 mediated cell destruction and prevent cell death. Tumour suppressor genes examples (different from oncogenes): NF-1 gene in neurofibromatosis BRCA-1 in breast and ovarian cancer Rb gene in retinoblastoma VHL gene in von Hippel Lindau P53 Li Fraumeni syndrome p53 : The p53 Gene is a tumor suppressor gene. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. Li Fraumeni syndrome predisposes patients to breast cancer and sarcoma. p53 is also a transcription factor and is not found only in malignant cells. It has a role in downregulating cell division and apoptosis. Fragile X syndrome is typified by delayed mental and motor development with associated seizures. Phenotypic features are prognathism, long face, high arched palate, large ears, cryptorchidism, hypotonia and mitral valve prolapse. Marfan's syndrome is an autosomal dominant condition associated with ocular abnormalities such as upwards lens dislocation and retinal detachment. Aortic regurgitation may occur due to aneurysmal dilatation a feature. Upper to lower body ratio (head- symphysis pubis : Symphysis pubis- toes) is decreased in Marfan Syndrome. Homocystinuria is an autosomal recessive disorder. Reduced activity of cystathionine synthase results in accumulation of homocysteine methionine. Osteoporosis and osteopetrosis are also seen in homocystinuria. In pre renal failure / Acute Tubular Necrosis (hypovolaemia, dehydration), the kidney attempts to retain sodium, hence urine sodium is <20mmol/l. The anion gap is normal (Na + K - Cl - Bicarb) - normal range is 10 - 16. Serum osmolality [2(Na + K) + urea + glucose]. Myosin is involved in striated muscle contraction. It forms filaments in a hexameric array of 2 heavy chains and 2 pairs of light chains.

Myosin heavy chain mutation is implicated in familial hypertrophic cardiomyopathy. HOCM and Carney complex are forms of myosin chain disorders. Enzyme deficiencies Gauchers disease Glucocerebrosidase deficiency Tay Sachs disease - Hexosaminidase A deficiency Niemann Pick disease Sphingomyelinase deficiency Metachromatic leukodystrophy - Arylsulphatase A deficiency Hurler's syndrome - Iduronidase deficiency Fabry's disease is an X-linked lysosomal storage disorder. It is caused by a deficiency of alpha-galactosidase A. Ceramide accumulation occurs in various organs including the heart, skin and nerves. The skin lesion is known as angiokeratoma corporis diffusum. Gaucher's disease is associated with the enzyme glucocerebrosidase. As a result, glucocerebroside accumulates, principally in the phagocytic cells of the body but also sometimes in the central nervous system neurones. Maple syrup urine disease (MSUD) is an aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration in the infant who is not treated for MSUD. Causes of Retinitis pigmentosa are: Kearn Sayre's syndrome Usher's disease Refsum's disease Lawrence Moon Biedl syndrome Alports's syndrome Friedrich's ataxia SIGNAL TRANSDUCTION G protein receptors are 7 transmembrane spanning receptors. Examples are: Muscarinic Ach receptor Adrenergic receptor (adrenaline) Retinal rhodopsin receptor FSH TSH ACTH GABA G protein second messenger abnormality is found in: Cholera pituitary adenoma McCune Albright syndrome lbright's hereditary osteodystrophy (pseudohypoparathyroidism) Examples of tyrosine Kinase receptors: Insulin PDGF VEGF Epidermal Growth Factor

 IGF-1 Macrophage colony stimulating factor

IMMUNOLOGY Complements C3 is activated by classical and alternative pathways. Classical pathway C1 (q,r,s), C2, C3, C3 are components C43b cleaves and activates C3 Activated by Ab-Ag complexes Alternative pathway C3, factor D, factor B, properdin are components C3bBb activates C3 Activated by endotoxin, bacterial cell wall Membrane Attack Complex Helps to penetrate cell membranes, leading to lysis Neisseria infection leading to meningococcal meningitis often occurs in patients with complement deficiencies of C5-9. Complements C5, C6, C7, C8, C9 form the Membrane Atttack Complex. C3a - mediates inflammation C3b - cleaves C5, opsonises, activates alternative pathway C5a chemotaxin, mediates inflammation Cell Adhesion Molecules are important regulatory molecules in inflammation and cell signalling/migration. ICAM-1 which is widely expressed is also implicated in ulcerative colitis and Crohn's Rather than T cell receptors, natural killer cells express adhesion molecules which allow adhesion to target cells. CD94 receptor is located in Natural Killer (NK) cells and is bound to the cell membrane. It enables NK cells to discriminate between healthy cells and pathogen infected cells Phagocytes have a role in recognition and elimination of microbes by reactive oxygen species or antigens by opsonisation

T cells Cytotoxic (CD8) T cells recognise MHC class I molecule antigens T helper (CD4) cells recognise MHC class II molecule antigens. MHC class I proteins are present on all nucleated cells. MHC class I molecules (rather than class II) allow self recognition. MHC class II proteins are only expressed on dendritic cells, macrophages, B-cells as antigen presenting cells . B cells usually require T cell help for full activation. B cells are activated in primary immune response which initially produce IgM. Deficiency of CD40 impairs class switching. Most T cell antigens have repetitive epitopes (e.g.LPS/endotoxin), which are able to cross link to B cell surface immunoglobulin to activate these cells. IL-1 causes pyrexia and local inflammation. Recombinant forms of interleukin receptor antagonists (IL-1Ra) are useful as disease modifying drugs in rheumatoid arthritis. IL-2, IL-4, IL-5 and IL-10 are commonly produced by T helper cells. Antibody production is promoted. Immature dendritic cells are stimulated to mature by T helper cells. Tumour necrosis factor can bind to either p55 or p75 receptors and activates nuclear factor kappa B (NFkB) transcription factor. It promotes interleukin activity and can induce apoptosis. TNF is procoagulant and can lead to thrombosis. TNF is produced by natural killer, T cells and macrophages. It enhances dendritic cell migration. It also increases adhesion molecule expression on vascular endothelium, allowing for increased permeability. IFN and IFN are antiviral cytokines. I FN is produced by natural killer and T cells. IFN and IFN (not ) bind to the same receptor known as type I receptors. IFN is used therapeutically in multiple sclerosis. IgG is the commonest antibody in the serum. There are 2 light and 2 heavy chains, making a total molecular weight of 150,000 kDa. It comprises 2 Fab fragments, and is divalent rather than monovalent. The reference range is 8-20 g/l. Systemic Mastocytosis is due to excessive mast cell stimulation. It leads to anaphylactic like states - urticaria, flushing and also GI symptoms such as diarrhoea and nausea. Mast cells are Ig E mediated but can be triggered by injury, drugs and complements. It is caused by mast cell release of histamine in the skin or connective tissue. Diagnosis can be confirmed by raised levels of urinary N-methyl imidazole, blood eosinophilia and thrombocytopenia. It classically presents with episodes of flushing, vomiting, diarrhoea and abdominal pain.

Hypersensitivity reactions Anaphylaxis is a type I reaction (atopic diseases). Good pasture's syndrome and Coomb's positive haemolytic anaemia are type II reaction (antibody to antigenic components). Serum sickness is a type III reaction (immune complex disease). An example of type IV reaction is contact dermatitis or allograft rejection (T cell mediated response). Common Variable Immunodeficiency (CVID) is a disorder characterized by low levels of serum immunoglobulins and an increased susceptibility to infections. A clear mode of inheritance is not defined (there are multiple modes) and there is a <10 % chance of passing on the disease. X linked immunodeficiency include SCID and Bruton's hypogammaglobulinaemia. Prions are glycoproteins which codes for a membrane protein. Prion proteins are usually resistant to protease digestion and are not broken down by heat. Prions do not contain genetic material. CJD, Kuru and scrapie are prion diseases. Prions are thought to have a role in cell signalling rather than DNA replication. Normal prion proteins are encoded by chromosome 20. PrPsc is characterised by increased pleated sheets. PrPsc proteins are anchored by glycoproteins (GPI). O2-Hb dissociation curve is shifted to the right when there is: an increase in CO2 increase in hydrogen ions (fall in pH) increase in temperature increase in lactate The curve is shifted to the left by increased carboxyhaemoglobin methaemoglobin fetal haemoglobin.

Bioavailability refers to absorption of the drug. Increased gastric emptying and induction of liver enzymes increases first pass metabolism and reduced bioavailability. Potency refers to the amount of drug usually needed to produce an effect, such as relief of pain or reduction of blood pressure. For instance, if 5 milligrams of drug A relieves pain as effectively as 10 milligrams of drug B, drug A is twice as potent as drug B. Efficacy refers to the potential maximum therapeutic response that a drug can produce. Frusemide eliminates more salt than hydrochlorothiazide, hence it has higher efficacy than hydrochlorothiazide. The difference in speed of acetylation is due to the amount (or activity) of the enzyme Nacetyltransferase available. Fast acetylation is a trait which is autosomal dominant inherited.

Drugs with zero order kinetics Alcohol Phenytoin Fluoxetine LIVER ENZYME INDUCERS (PCBRAS) Phenytoin Carbamazepine Barbiturates Rifampicin Alcohol Sulphonylureas LIVER ENZYME INHIBITORS (OAAK DEVICCES) Omeprazole Amiodarone Allopurinol Ketoconazole Disulfram Erythromycin Valproate Isoniazid Ciprofloxacin Cimetidine Ethanol Sulphonamides Drug induced lupus: procainamide isoniazid chlorpromazine penicillamine sulfasalazine hydralazine methyldopa quinidine Drugs which can cause gynaecomastia are : digoxin oestrogens spironolactone cimetidine verapamil nifedipine Drugs causing galactorrhoea are: Oral contraceptive pills Phenothiazines such as chlorpropramide and thioridazine Metoclopramide

Bromocriptine The drugs most commonly implicated in SIADH are: cyclophosphamide chlorpromamide carbamazepine clofibrate thiazide diuretics vincristine vinblastine phenothiazines tricyclic antidepressants SSRIs Drugs producing hypercalcemia include: lithium, alkaline antacids DES, Thiazides estrogens progesterone MISCELLANEOUS DRUGS Common side effects of Selective Serotonin Reuptake Inhibitors (SSRIs) are nausea, vomiting, diarrhoea, appetite and weight loss, sexual dysfunction and deranged liver function tests. Similarly, the common side effects of fluoxetine are :anxiety or nervousness; decreased appetite; diarrhoea; drowsiness; headache; increased sweating; nausea; tiredness or weakness; trembling or shaking; insomnia. Amiodarone blocks conversion of T4 to T3 and affects pituitary thyroid axis. The following changes in thyroid function tests occur within 3 months of starting amiodarone and are not indicative of thyroid disease: increase in TSH up to 20mU/L increase in T4 to upper limit of normal decreased T3 levels. Anticholinergic syndrome occurs following overdose with drugs that have anticholinergic activity. Examples of these are tricyclic antidepressants, antihistamines and atropine. Features include flushed skin, urinary retention, tachycardia, mydriasis (dilated pupils) and agitation. Physostigmine, a reversible inhibitor of acteylcholinesterase, is effective in treating anticholinergic symptoms but there is a significant risk of cardiac toxicity (bradycardia, AV conduction defects and asystole) with the drug. Bisphosphonates acts at the cellular level. They act directly or indirectly on the osteoclasts. The effect can be on the formation of osteoclasts and/or on their activity. A decrease in osteoclast number can occur either through direct action on osteoclast precursors, or indirectly by stimulating the osteoblasts to produce an inhibitor of osteoclast formation. Osteoclast inactivation is associated with bisphosphonate uptake from the bone surface. -interferon is a long term treatment (as opposed to steroids for acute relapses) which is of benefit only in the relapsing remitting form (about 40% of MS patients have this form), and slows progression of disability and reduces demyelinating lesions.

Aspirin toxicity causes symptoms of nausea, vomiting, headache, confusion and tinnitus or hearing difficulties. Major side effects of carbimazole are: agranulocytosis, thrombocytopaenia, acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome and vasculitis. It may cause neutropenia in 1 in 800 patients. Clozapine induced agranulocytosis occurs in about 1% to 10% of patient who take clozapine. Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive clozapine again. Hyperkalaemia, hirsutism, tremors, hypertension, nausea and vomiting, headache, gum hypertrophy, parasthesiae and hypomagnesaemia are side effects of ciclosporin. Disulfiram (antabuse) acts by causing raised acetaldehyde levels. This causes unpleasant effects. Metronidazole and disulfram synergism may lead to psychosis. Digoxin is slowly absorbed, hence peak effects can be delayed for up to half a day after an overdose. Visual disturbance, nausea and vomiting, tachy and bradyarrhythmias can occur with an overdose. Activated charcoal decreases absorption. Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the tumor necrosis factor receptor (TNFR) linked to a human IgG1. The receptor binds to TNF, it is not a monoclonal antibody. It is licensed for juvenile rheumatoid arthritis and juvenile idiopathic arthritis. Side effects are septic arthritis, demyelination, pancytopenia, aplastic anaemia and congestive heart failure. . Infliximab is a monoclonal anti-TNF antibody. Ezetimibe acts by prevent cholesterol absorption from the small intestine. Typically it reduces LDL-cholesterol by approximately 20%, triglycerides by up to 5% and raises HDL-cholesterol by approximately 5%. Ezetimibe is currently licensed for use in combination with a statin in patients who fail to reach desired lipid profiles or as monotherapy in patients intolerant to a statin. Thiazides block Na+ and Cl- reabsorption in the distal tubule. There is usually passive Na+ and Cl- co transport. With this blocked, natriuresis occur. The distal convoluted tubule accounts for 5% of total sodium chloride reabsorption. Thiazides elevate LDL cholesterol, reduce urinary calcium excretion and can cause impotence. Hypercalciuria can be treated with thiazides. Thiazides can cause thrombocytopaenia, hypokalaemia (blocking NaCl channels), and hyperuricaemia. Frusemide acts on the thick portion of the ascending loop of Henle. It inhibits Na+ and Cl- reabsorption there via Na+, K+, -ATPase-dependent pump. Owing to the large NaCl absorptive capacity of the loop of Henle, agents that act at this site produce a diuretic effect much greater than that seen with other diuretic groups.

Insulin glargine is a long-acting insulin analogue, there is a smooth, prolonged absorption profile with no peaks. As such, it is a long-acting agent, suitable for providing a basal level of insulin which mimics the normal physiological state. Its smooth profile reduces the risk of hypoglycaemia, and when given at night, provides good control of the fasting blood glucose. Lofexidine a centrally acting alpha-2 adrenergic agonist, was launched specifically for symptomatic relief in patients undergoing opiate withdrawal programmes. In open studies in small groups of methadone dependent patients, lofexidine treatment enabled successful detoxification (defined as remaining drug free for 10 days after the last methadone dose) in greater than 65% of patients.

Mesalazine can cause neutropenia. It works in IBD by release in the terminal ileum. Mesalazine is given in the acute attacks in Crohn's disease. Sulfasalazine (sulphapyridine and 5-amino-salicylic acid) is used in rheumatoid arthritis. Penicillamine is a DMARD which can is used in Rheumatoid arthritis, Juvenile chronic arthritis and as a copper binder in Wilsons hepatolenticular degeneration. It is also used in PBC, chronic active hepatitis and cystinuria. It can cause aplastic anaemia and thrombocytopenia, proteinuria and loss of taste. Penicillamine is associated with drug-induced lupus, Goodpastures syndrome, myasthenia, myositis and Stevens-Johnson syndrome. Orlistat is an inhibitor of gastrointestinal lipases, leading to reduced fat absorption. It is licensed for patients with BMI > 28 with associated risk factors, a weight management programme should be in place. Use is not recommended for more than 2 years. Quetiapine is indicated for the management of the manifestations of schizophrenia. The commonest side effects (>5%) are excessive sedation, dizziness, dry mouth, postural hypotension, and elevated ALT. Theophylline is metabolised in the liver. Plasma theophylline levels are increased in heart failure, cirrhosis of the liver, viral infections, elderly patients, and by drugs that inhibit metabolism of theophylline. The plasma levels of theophylline are decreased in smokers, chronic alcoholism and by drugs that induce liver metabolism. Metformin a biguanide. Its mode of action is thought to be multifactoral and includes delayed uptake of glucose from the intestinal tract, increased peripheral glucose utilisation mediated by increased insulin sensitivity and inhibition of increased hepatic and renal gluconeogenesis. In metformin overdose, main symptoms of toxicity include gastrointestinal upset due to a severe lactic acidosis. Hypoglycaemia is not often seen in metformin overdose. If lactic acidosis occurs following overdose, mortality can be high. Management is gastric decontamination and use of activated charcoal if appropriate, and correction of acidosis with 8.4% sodium bicarbonate. Haemodialysis can be considered in severe cases. Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. Sumatriptan is a 5HT1 agonist and may be useful in the treatment of acute migraine attacks. is available in injectable, intranasal, and oral formulations. Ergotamine tartrate is also effective in acute migraine. Propanolol, valproate, NSAIDs,

amitriptyline, pizotifen and gabapentin are effective as prophylactic drugs in migraine. IMMUNOSUPPRESANTS Immunosuppresants: Corticosteroids act on cytosolic rather than cell membrane receptors. Both mycophenolate and azathioprine Approximately 1 in 300 Caucasians have thiopurine methyl transferase (TPMT) deficiency. TPMT is the enzyme that metabolises 6-mercaptopurine and its deficiency results in high risk of azathioprine toxicity. Azathioprine is used when steroid withdrawal causes recurrent relapse. Bone marrow suppression (low white cell count) and pancreatitis are side effects of azathioprine Methotrexate: Binding of methotrexate to dihydrofolate reductase reduces nucleotide synthesis as well as amino acids serine and methionine. Folinic acid rescue is usually given after methotrexate therapy (e.g. 24 hours) to reduce myelosuppression side effects. Methotrexate is associated with interstitial pneumonitis. This is rare but a serious complication. Chest radiography reveals a diffuse interstitial or mixed interstitial and alveolar infiltrate, with a predilection for the lower lung fields. Common side effects of gold are mouth ulceration, leucopenia, proteinuria and skin rashes. Hydroxychloroquine can cause renal toxicity. Sulphasalazine causes nausea and vomiting, leucopenia and deranged liver function. Allopurinol specifically inhibits xanthine oxidase and prevents metabolism of azathioprine to mercaptopurine. This action causes increased toxicity of azathioprine. TOXICITY / ADVERSE EFFECTS Common symptoms of lithium toxicity (can occur at levels greater than 1.1 mmol/l) are nausea and vomiting, diarrhoea, disorientation, tremors and ataxia. Lithium can cause hypercalcaemia and hypothyroidism along with a goitre, fine tremor, weight gain, diabetes insipidus and cardiac arrhythmias. Gammahydroxybutyric acid causes hypernatraemia, metabolic acidosis, hypokalaemia, hyperglycaemia. Hypotension/shock, glucose >8.3 mmol/l, white cell count > 15, haemetemesis and decreased consciousness are features of severe iron poisoning. The primary symptoms of mercury poisoning are vague psychiatric ones. Short-time memory can deteriorate. Organic mercury can cross the blood-brain barrier and cause

irreversible nervous system and brain damage, e.g., loss of motor control, numbness in limbs, blindness, and inability to speak. Methaemoglobinaemia can be caused either by a genetic defect in red cell metabolism or haemoglobin structure, or acquired by a variety of drugs and toxins. Common drugs dapsone, nitrates, prilocaine, antimalarials, sulphonamides and dyes. Domestic causes of acquired methaemoglobinaemia include ingestion of food and water high in nitrites and nitrates exposure to aniline dyes in dyed blankets, laundry markings, freshly dyed shoes, red wax crayons and cleaning solution. Standard pulse oximeters give spuriously low readings in the presence of excess methaemoglobin. Methylene blue is indicated in any patient with symptoms and/or signs of hypoxia (mental changes, tachycardia, dyspnoea, chest pain). It is contraindicated in G6PD deficiency. High flow oxygen should be administered. Carbon monoxide poisoning is produced by the incomplete combustion of carbon containing fuels such as gas, coal, oil, wood and coke. Headache is the most common symptom (90%) followed by nausea & vomitting, vertigo, alteration in consciousness and weakness. The cherry red skin colour occurs when COHb concentration exceeds 20% but it is rarely seen in life. Pulse oximetry gives falsely high oxygen saturation sand it is not recommended. Phenytoin toxicity can cause: sedation slurred speech nystagmus ataxia vertigo Long term side effects of phenytoin are: gingival hypertrophy hirsutism acne coarseness of facial features Common drugs which can precipitate a porphyria attack are: Barbiturates Sulfonamides chloroquine steroids

Barbiturate withdrawal in an habitual abuser a well recognised cause of fits. Benzodiazepine elevates the level of an inhibitory neurotransmitter, GABA, therefore it serves as a tranquilizer. Barbiturates are prescribed as anticonvulsants, sedatives, and general anesthetics. Commonly abused barbiturates include amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). These drugs depress the respiratory and nervous system functions. Symptoms of withdrawal syndrome appear 12-20 hours after the last dose; they include anxiety, irritability, elevated heart and respiration rate, muscle pain, nausea, tremors, hallucinations, confusion, and seizures.

Chronic cocaine use can result in erectile dysfunction, ejaculatory dysfunction, hypersomnia, excitement, emotional instability, restlessness, irritability, apprehension, inability to sit still, teeth grinding, cold sweats, tremors, twitching of small muscles Severe anxiety and paranoid hallucinations, mania, and psychosis can also occur with cocaine use. Features of acute MDMA (ecstasy) toxicity include agitation, tachycardia, hypertension, dilated pupils, sweating, hyperthermia, disseminated intravascular coagulation (DIC), rhabdomyolysis and acute renal failure. Theophylline poisoning results in profound Hypokalaemia, SVT and VT, vomiting, agitation and convulsions. Activated charcoal is the method of choice for elimination. Diazepam may be used to control convulsions and Propanolol may help tachycardia and reversal of hyperglycaemia (however, beware of using it in asthma). Agents not adsorbed by activated charcoal include: metals (lithium, iron) hydrocarbons and solvents alcohols Neuroleptic malignant syndrome is characterized by fever, muscular rigidity, labile blood pressure, altered mental status, decreased conscious level and autonomic dysfunction. Although potent neuroleptics (eg, haloperidol, fluphenazine) are more frequently associated with NMS, all antipsychotic agents may precipitate the syndrome. For example, these agents are prochlorperazine, promethazine , clozapine , risperidone . Dystonic reactions usually subsides within 24 hours following cessation of treatment and can be treated with procyclidine 5-10 mg i.m. They are well-recognized with dopamine receptor antagonists (neuroleptics). Phenothiazines, prochloperazine, haloperidol and metclopramide are examples of drugs which can cause dystonic reactions. Oculogyric Crisis is one of the acute dystonic reactions. It is the most common of the ocular dystonic reactions (which include blepharospasm, periorbital twitches, and protracted staring episodes). Priapism as a side effect is associated with phenothiazines (chlorpromazine), haloperidol, trazodone and alpha blockers (prazosin). MORPHINE EQUIVALENT DOSES 100 mg of MST has the equivalent dose of 25 ug/hr of fentanyl over a day. A 24 hour diamorphine dose should be 1/3 of the 24 hour morphine dose. The breakthrough dose of short acting morphine such as oramorph should be 1/6th of the total 24 hour dose of morphine. The equivalent dose of oral oxycodone 0.833 is to diamorphine SC 1.3 (about 2/3).

PREGNANCY Trimethoprim is a folate antagonist and can increases the risk of neural tube defects. There is relative contraindication for ciprofloxacin in pregnancy due to the possible teratogenic effect. Augmentin, cefaclor, nitrofurantoin and metronidazole are safe in pregnancy. Carbimazole crosses the placenta and can cause nail/finger abnormalities. Propylthiouracil is commonly used in pregnancy instead of carbimazole due to the risks of neonatal hypothyroidism with carbimazole. Warfarin in the first trimester can cause fetal hypoplasia of the nose and limbs. After this period warfarin is associated with neurological damage mental retardation, microcephaly, optic atrophy and blindness. There is an option to convert from heparin to warfarin in the third trimester, but the patient will have to be re-converted back to heparin before delivery.

Assuming normal distribution - 99% of subjects are within 3 standard deviations of the mean 95% of patients within 2 standard deviations 68% are within 1 standard deviation Example: The mean Hb value for a group of 150 patients is 15 g/dl. The standard deviation is 2 g/dl. 95% of patients would have a Hb between 11 and 19. Z scores can be used instead of standard deviation to estimate distribution. If an observation lies 1 standard deviation away from the mean, its z score is 1. Hence, a score of 2 is 2 standard deviations more than the population, and a score of -2 is to standard deviations less than the mean. Standard Deviation is the square of variance. Standard error of the mean is the standard deviation of the sampling distribution of the mean - which gives an estimate of how close the sample mean is to the true population mean. It increases with sample size and increases with stand deviation. The S.E.M. is the standard deviation divided by the square root of the sample size SEM = / N where is the standard deviation of the original distribution and N is the sample size). Coefficient of variation is expressed in %. The definition coefficient of variation V = SD/mean. In this example 15/150 = 10%. It is a statistical measure of the deviation of a variable from its mean. Sensitivity is the probability that a test will be positive when a patient has the condition. Alternatively, it is the number of true positives detected by the test divided by the number of all true positives in the population tested. Specificity is the probability that a test will be negative when a patient does not have the condition. Alternatively it is the number of true negatives detected by the test divided by the number of all true negatives in the population. Positive predictive value suggests the probability that if a test is positive, it is true

The null hypothesis states that there is no difference between treatments. A type 1 error occurs when the null hypothesis is falsely rejected. This means that the study claims to find a difference that does not really exist. A type 2 error occurs when the null hypothesis is falsely accepted. This means that although it is suggested that there is no difference between two groups, the study is actually too small to detect a difference. Comparing two groups, all who have a risk factor, the relative risk is the ratio of those who had the disease, compared to those who did not have a disease. For example, the relative risk in a group of patients is the ratio of those who had CVA in a hypertension group compared to those who had CVA without hypertension (e.g. 10 patients / 2 patients = 5). The attributable risk is the difference in incidence of a disease, among patients who have or do not have a risk factor. It is expressed in %. For example, 20% with hypertension had CVA and 5% without hypertension had CVA, hence 20% - 5% - 15%. Another example, if a drug reduces the incidence of stroke from 10% to 5%. The relative risk reduction (RRR) is 50%. The absolute risk reduction (ARR) is 5%. The number needed to treat (NNT) is the total divided by the absolute risk reduction, which is 100% / 5% = 20. NNT is defined as number needed to treat to prevent 1 death. Secondary prevention does treat patients with pre-existing disease, such as heart attack. It also involves identification of patients who are high risk of further development of cardiovascular disease Chi-squared tests are used to compare percentages or proportions of categorical data. Data such as the above can be organised into a 2 x 2 contingency table. From the chisquared value a p value is read off a statistical table (depends on degree of freedom) to give the degree of significance. The paired students t test can be used to compare two groups of patients with parametric data (Null hypothesis being that any difference is due to chance). Parametric means that the data will be of normal distribution and parallels the normal or bell curve). In addition, it means that numbers can be added, subtracted, multiplied, and divided. Normally distributed data can be compared with a Students t-test. Skewed continuous data can be compared with a Wilcoxon rank-sum test or a MannWhitney U-test. They should be described with a median and range, but NOT a mean. The tests are also known as non parametric tests. Logistic regression allows one to predict a discrete outcome, such as group membership, from a set of variables that may be continuous, discrete, dichotomous, or a mix of any of these. ANOVA is an example of a logistic regression analysis. Case control studies are not good at identifying rare causes. In order to identify whether a rare exposure causes a disease then the appropriate design is a large cohort study, where one group with the particular exposure of interest is compared with a control group without that exposure. The advantage of case control studies is that they can be used with

rare diseases and can examine multiple risk-factors. Poor control selection often makes a case control study uninterpretable. Crossover trials are designed where a patient can have one drug, have a washout period and then a second drug. It is applicable to chronic conditions, such as multiple sclerosis and not acute conditions such as MI requiring thrombolysis. Intention to treat reduces bias by including the data from original allocation of treatment, e.g. analyzing the patient in a treatment group even if they did not complete the trial (dropped out because of side effects).

CARDIOVASCULAR EXAM The second heart sound comprises of aortic (A2) and pulmonary (P2) component. In LBBB, the aortic closure is delayed because the left ventricle contracts later. This then causes reversed splitting (A2P2 P2A2) if the second heart sound. LBBB and left heart strain in HCM and aortic stenosis can cause reversal of A P second
2 2

heart sounds. Also, in type B wolf parkinson white syndrome, early activation of the right ventricle through an accessory pathway can cause P2 to close prematurely. Patent ductus arteriosus is another cause. The third heart sound is caused by early diastolic filling due to ventricular relaxation, shortly after closure of the aortic valve (corresponds to Y descent in JVP). It may be normal in children and young /middle aged adults. Causes of an abnormal third heart sound are: Left ventricular failure Severe MR and TR VSD, PDA Constrictive pericarditis Hypertrophic cardiomyopathy Dilated cardiomyopathy AV fistula thyrotoxicosis Causes of an abnormal fourth heart sound are: Causes of raised JVP are: Congestive cardiac failure SVC obstruction Constrictive pericarditis Anaemia Tricuspid regurgitation Pulsus paradoxus is defined as an inspiratory systolic fall in arterial pressure of 10mmHg. It not only occurs in cardiac tamponade, but also in massive PE, severe COPD and hypotension/shock. Cannon a waves occur when the atria and ventricles contract at the same time. The causes are complete AV block, ventricular tachycardia and AV nodal reentry tachycardia

CARDIAC ANATOMY The left internal mammary artery supplies the anterior chest wall. It has been shown to be superior to saphenous vein grafts (from aorta to LAD) in staying patent and hence is now the choice artery (LIMA to LAD) graft. Although circumflex and right coronary arteries are usually grafted with veins, the right internal mammary arteries (RIMA) are sometimes used to graft the RCA. The circumflex artery gives off obtuse marginal branches and the LAD gives off diagonal branches. The intermediate artery is not always present, it is a variant artery which is between the LAD and circumflex artery, and occasionally dominant instead of the circumflex. The coronary sinus predominantly drains venous blood from the left ventricle and receives approximately 85 percent of coronary venous blood. It receives blood from the the marginal, posterior left ventricular, anterior interventricular veins and the great cardiac vein. The blood finally drains into the right atrium. The posterior descending artery is often (85%) a branch of the right coronary artery. The sinus node artery is a branch of the right coronary artery in 60% of cases. The AV node is supplied by the posterior descending coronary artery. ARRHYTHMIAS Atrial flutter most commonly presents with 2:1 block, which means atrial rate of 300 but ventricular rate of 150. Ischaemic chest pain may occur due to the tachycardia. Carotid sinus massage can sometimes terminate or slow the tachycardia. DC cardioversion should be performed if the patient is cardivascularly unstable. Atrial flutter is commoner in patients with dilated left atrium or in congenital/structural heart disease. Differentiating SVT from VT Features that favour VT are : QRS of > 140ms, cannon a waves on JVP fusion and/or capture beats dissociated p waves, history of ischaemic heart disease, right bundle branch block with left axis deviation, concordance of the QRS complexes in the chest leads HR >170 beats per minute. In a patient who is stable with sustained ventricular tachycardia, the options are intravenous lignocaine, intravenous amiodarone. IV magnesium sulphate (18 / 20 mmols or 5g) is often helpful in helping to cardiovert. If the patient were unstable then he needs to be DC cardioverted immediately (with or without general anaesthetic). The criteria for ICD insertion are: 1) patients with LVEF <40% with non sustained VT

2) patients with sustained VT 3) patients who have had any VT or VF leading to cardiac arrest 4) cardiomyopathy and ventricular arrhythmias 5) patients with previous MI and ejection fraction <30% The MADIT II trial showed that in patients with a previous MI and reduced left ventricular ejection fraction (<30%), the prophylactic use of an ICD, in addition to medications, significantly reduced the risk of death. The first form of second degree heart block, Mobitz type I (Wenkebach) is due to progressive prolongation of PR interval and then missing a beat. Mobitz type II second degree heart block can occur with 2:1 (only 1 QRS is conducted for 2 p waves) or 3:1. RBBB (not LBBB) with left anterior hemiblock (or left axis deviation) is called bifascicular block. If first degree heart block was also present, then it is known as trifascicular block. PROLONGED QT A QT interval of >0.45 is prolonged. DRUGS causing PROLONGED QT tricyclic antidepressants (eg. amitryptiline) quinidine, erythromycin, amiodarone, phenothiazines (chlorpropramide), antihistamines (terfenadine) grapefruit juice sotalol METABOLIC causes of PROLONGED QT Hypokalaemia Hypocalcaemia Hypomagnesaemia Hypothermia Hypothyroidism A dominant R in lead V1 on the ECG is associated with : -primary pulmonary HT Right bundle branch block (RBBB) (including Ebstein's anomaly -Wolf-Parkinson-White syndrome Type A -Dextrocardia -Posterior MI -Duchene muscular dystrophy MYOCARDIAL INFARCTION Absolute contraindications to thrombolysis include: previous haemorrhagic stroke ischaemic CVA within 1 year suspected aortic dissection active bleeding <10 days BP>180/110 neurosurgical procedure < 6 months ago

Relative contraindications include major surgery or bleeding within 6 weeks pregnancy known bleeding diathesis severe uncontrolled hypertension Proliferative diabetic retinopathy Troponins tend to be elevated for up to 14 days. CK-MB comes down to normal level within 48-72 hours, and is the most specific of the CK enzymes. Pulmonary embolus, arrhythmias, myocarditis and right heart disorders are also known to elevate troponins. HYPERLIPIDAEMIAS The characteristics of familial hypercholesterolaemia are: autosomal dominant condition increased LDL concentrations reduced HDL concentrations reduced numbers of LDL receptor cardiovascular disease tendon xanthomatas In familial hypercholesterolaemia characteristically total cholesterol is > 7.5mmol/L, LDL-cholesterol is > 5.0 mmol/L and triglyceride is < 2.3 mmol/L. It is due to an LDL receptor defect.
THE PRIMARY HYPERLIPIDAEMIAS: THE FREDERICKSON CLASSIFICATION

Type II hyperlipidaemia the most common primary hyperlipidaemia. The picture is similar to familial hypercholesterolaemia but milder. It is characterised by increased levels of LDL-cholesterol (> 4.0 mmol/L). Triglyceride levels are < 2.3 mmol/L. Type IIa hypercholesterolaemia causes heart disease as there is predominantly raised cholesterol and high LDL. There is also increased triglycerides cause eruptive skin xanthomas, lipaemia retinalis (white TG deposits in the retina) and pancreatitis. Cholesterol has an affinity for deposition around the tendons, tendon xanthoma is characteristic of hypercholesterolaemia. Type II b hypercholesterolaemia also causes elevated cholesterol and triglycerides. Type III hyperlipidemia is when cholesterol and triglyceride are both increased, and is associated with atherogenesis. Homozygosity for the E2 genotype (E2/E2) is found in most patients with type III hyperlipidemia. The palmar striae (palmar xanthomata) are considered pathognonomic for the disorder and occur in less than 50% of patients but tubero-eruptive xanthomata, typically on the elbows and knees, as

well as xanthelasma have been described. The underlying biochemical defect is one of a reduced clearance of chylomicron and VLDL remnants. Type IV hyperlipidemia causes an isolated hypertrigIVceridaemia. There is normal or slightly raised plasma cholesterol. There are increased triglyceride levels due to increased VLDLs Type I and V hyperlipidaemia have lipoprotein lipase defects, and lead to raised chylomicrons and triglyceride levels. Eruptive xanthomas in the skin are typical of triglyceridaemia. Alcohol abuse, pancreatitis and hypertriglyceridaemia are associated. Both type I and type IV are triglyceridaemic states. Triglycerides cause turbid serum. List of causes of raised triglycerides are: nephrotic syndrome hypothyroidism biliary obstruction steroids diabetes mellitus renal failure thiazide diuretics oral contraceptive pill lipodystrophies and glycogen storage disease (Von Gierke's) Chylomicrons are triglyceride-rich lipoproteins (75%-95% of their core lipid is triglyceride) made in the small intestine from ApoB-48 (apoliproprotein). VLDL are made in the liver from ApoB-100. Ventricular septal defect (VSD) is the commonest form of congenital heart disease. Maladie de Roger is a loud systolic murmur despite a small VSD. Antibiotic prophylaxis should be used at all times. The systolic murmur does become softer as right heart pressures increase and a right to left shunt may develop in Eisenmenger's syndrome (leading to cyanosis). PERICARDIAL DISEASE Acute Pericarditis causes: saddle shaped ST elevation on ECG, raised Troponin Coxsackie B is the commonest cause. Other causes are HIV, diphtheria, Chagas disease, Lyme disease, SLE and arsenic poisoning. In constrictive pericarditis, because the atria are equilibrated with the ventricles in early diastole, the jugular venous waveform and right and left atrial waveforms show a prominent and deep y descent. The systolic x descent is usually also present. The main feature in chronic constrictive pericarditis is restriction of diastolic filling of ventricles. This may lead to the pericardial knock during ventricular filling. Ascites can occur due to chronic venous congestion and liver cirrhosis. Poor ventricular filling can lead to a low pulse pressure.

Summary signs of constrictive pericarditis are: rapid x and y descent ascites hepatomegaly ankle oedema pulsus paradoxus can occur but is less common especially in chronic constrictive pericarditis Cardiac tamponade This pattern of venous return in chronic constrictive pericarditis contrasts with that in cardiac tamponade, in which the venous pressure tracing shows absence of diastolic y descent (i.e. there is a deep x descent but y descent is absent) . Cardiac tamponade also causes a raised JVP, Kussmauls sign and pulsus paradoxus. Summary signs of cardiac tamponade are: rapid x descent Kussmauls sign pulsus paradoxus CARDIOMYOPATHY In hypertrophic cardiomyopathy (HCM), there is decreased compliance due to the disorientation of myosin fibres. 40% of patients carry mutations of cardiac beta Myosin heavy chain on chromosome 14. Maneouvres which decrease venous return will increase the intensity of the murmur (valsalva baroreceptor mediated fall in cardiac output, standing, nitrates). Maneouvres which increase venous return will decrease the murmur as this overcomes the obstruction (squatting, long term beta blockers). In summary, the murmur in HCM: increases in valsalva Maneouvre increases with standing decreases with exercise decreases with squatting Nitrates are best avoided because they are vasodilators which may cause hypotension with the condition. Beta blockers and calcium channel blockers help increase end diastolic filling and treat symptoms but have no effect on risk reduction of sudden death. Amiodarone improves survival. Restrictive cardiomyopathy: Echocardiography showing no pericardial effusion and stiffness suggests restrictive rather than constrictive cardiomyopathy. The transmitral dopplers on the echo may show E/A wave reversal and high velocities which may suggest restrictive picture. This may be due to infiltration due to haemochromatosis, endomyocardial fibrosis, sarcoidosis, myeloma, lymphoma or connective tissue disease.

In hypertrophic cardiomyopathy (HCM), there is decreased compliance due to the disorientation of myosin fibres. Maneouvres which decrease venous return will increase the intensity of the murmur (valsalva baroreceptor mediated fall in cardiac output, standing, nitrates). Maneouvres which increase venous return will decrease the murmur as this overcomes the obstruction (squatting, beta blockers). Beta blockers and calcium channel blockers help increase end diastolic filling and treat symptoms but have no effect on risk reduction of sudden death. Amiodarone improves survival. Over a hundred different mutations in at least nine different genes, all encoding sarcomeric polypeptides, have been associated with hypertrophic cardiomyopathy (HCM). ENDOCARDITIS Oslers nodes, which are small reddish tender areas on the pulp of fingers or toes. Janeway lesions are reddish spots on fingers or toes, but are painless. A definite diagnosis of endocarditis (Duke's criteria) is achieved when 2 major criteria are present, or 1 major and 3 minor criterias. Major criteria: blood culture positive for typical organisms persistent bacteremia positive ECHO for vegetations abscess or valve dehiscence Minor criteria: valvular heart disease or IV drug user fever greater than 38C vasculitis skin lesions suggestive ECHO (but not definite) positive blood culture In a patient with prosthetic valve, staph epidermidis (one of the coagulase negative staph) and Strep viridans are most common. Strep bovis, and enterococcus are the other organisms which commonly cause endocarditis. One of the major dangers with aortic valve endocarditis is an aortic root abscess. This can lead to prolonging of the PR interval by erosion into the adjacent AV node, hence daily ECGs are useful for monitoring. Marantic endocarditis: this disorder results in the deposition of fibrin on the valve leaflets on either side of the heart, but especially the left side. The vegetations are sterile and small (1-5 mm). This form of noninfective endocarditis can be seen in persons who are very debilitated or in those who have a hypercoagulable state.

Major criteria for Rheumatic fever are: Chorea carditis polyarthritis erythema marginatum nodules (subcutaneous) Minor criteria are: fever arthralgia raised inflammatory markers previous rheumatic fever prolonged PR on ECG 2 major or 1 major and 2 minor satisfy criteria for Rheumatic Fever. The HACEK organisms are: Haemophilus species (H. aphrophilus, H. paraphrophilus, H. parainfluenzae) Actinobacillus actinomycetemcomitans Cardiobacterium hominis Eikenella corrodens Kingella These are gram negative bacilli which are responsible for 5-10% of cases of infective endocarditis (IE) involving native valves and are the most common cause of gramnegative endocarditis among persons who do not abuse intravenous drugs. HYPERTENSION Treatment is recommended for a blood pressure of > 160/100 in patients without end organ damage, by the British Hypertension Society. The British Hypertensive Society guidelines suggests either a Diuretic(D) or Calcium channel blocker(C ) for an older or black patient Malignant hypertension can present with pulmonary oedema, chest pain, headache, visual disturbance and also seizures. A fundoscopic examination may reveal flameshaped retinal hemorrhages, soft exudates, or papilledema. Sodium Nitroprusside has an immediate onset of action and short half-life. It acts by causing relaxation of vascular smooth muscle, resulting in vasodilation and inotropy. The dose is 0.25-10 mcg/kg/min IV. IV hydralazine, beta blockers and calcium channel blockers can also be used. Methyldopa is the safest agent to use in the first and second trimester of pregnancy. Beta blockers may cause intrauterine growth retardation. ACE inhibitors have also been suggested to have teratogenic effects. Acute hypertensive crisis of phaeochromocytoma : IV administration of sodium nitroprusside, nitroglycerine, or phentolamine can be used. Preoperatively, phenoxybenzamine preoperative adrenergic-blockade of a1 and a2 receptors with phenoxybenzamine (10-30 mg twice daily), or a1 receptors with prazosin (starting with 1 to 2 mg three times daily. Beta blockers can be useful for arrhythmias, but should not be commenced before alpha blockers because b-blockade alone can cause marked hypertension. Significant outflow tract obstruction, advanced heart block, hypertension > 180 mmHg systolic, and unstable angina are all contraindications towards Exercise Testing.

DRUGS Digoxin toxicity can occur especially with renal impairment. It typically causes nausea & vomiting. ST depression occurs along with bradycardia on the ECG. The patient may also get xanthopsia (yellow vision). Aspirin blocks the synthesis of COX1 and COX2 enzymes. This leads to a reduction in the prostaglandin PGG2, PGH2 thromboxane TXA2 synthesis . This leads to platelet aggregation. Aspirin does reduce urate secretion in the renal tubules and can increase risk of gout. Brain or B type natriuretic peptide is increasingly used as a marker of congestive heart failure. It has high specificity for the condition. It is released by ventricular cardiomyocytes due to stretch as part of the pathophysiology of cardiac failure. GIIB/IIIA inhibitors such as Reopro or Tirofibran have a treatment role in NSTEMI Heart failure trials Bisoprolol (CIBIS II trial), spironolactone (RALES trial), enalapril (CONSENSUS) and nitrates and hydralazine (V-HEFT) have all been shown to improve mortality in chronic heart failure. Flecainide is a class Ic antiarrhythmic drug. It helps restoration of sinus rhythm and prevent recurrence of AF. Flecainide may prolong QT interval. The drug was used in the Cardiac Arrhythmia Suppression Trial (CAST) trial, and was associated with increased mortality in patients with ischaemic heart disease. Sotalol has class II (beta-blocker) and class III antiarrhythmic actions. Nifedipine is a dihydropyridine. The mechanism of action is smooth muscle relaxation and reduction in peripheral vascular resistance.

MISCELLANEOUS Aortic Dissection Hypertension should be treated with an infusion such as labetalol. Aortic regurgitation and pericardial effusion (haemopericardium) suggest dissection down to the aortic root. These features, or persisting chest pain suggest that the patient requires prompt surgery.

Aortic dissection can present with pain radiating to the epigastric region or back. If the dissection flap involves close to the aortic root, then the coronary flow can be affected, causing either inferior MI in right coronary artery or anterior MI in left anterior descending artery involvement. Cardiac tamponade can also be caused by dissection (blood flowing into pericardial space) and leading to a raised JVP and pulsus paradoxus. Dissection of the aorta is associated with hypertension, cocaine abuse, trauma, pregnancy, aortitis as seen in syphilis, Marfans, Ehlers-Danlos and other connective tissue disorders. A bicuspid aortic valve may be present in up to 1% of the population. It is more common in men. 5% of bicuspid aortic valves are associated with coarctation of the aorta. The clinical signs consistent with severe aortic stenosis are: Slow rising pulse character 4th heart sound Soft aortic 2nd heart sound Systolic thrill Extended length of murmur in systole Causes of aortic regurgitation are bicuspid aortic valve, calcific degeneration, Williams syndrome (elfin facies, congenital heart disease, cognitive impairment), endocarditis, seronegative spondyloarthritidies, connective tissue diseases (Marfan's, osteogenesis imperfecta), aortitis. Coarctation of the aorta is associated with Turners syndrome, neurofibromatosis, bicuspid aortic valve, and more weakly with VSD and ASD. Stroke may result from hypertension or from associated berry aneurysms. It is more common in males. Notching of ribs is seen, typically between 3 to 8. With ASD, a Primum defect causes RBBB and LAD, whilst Secundum causes RBBB and RAD on the ECG. Secundum ASD is associated with Holt-Oram syndrome(triphalangeal thumb and radial abnormalities). Brugada Syndrome is an autosomal dominant disease with variable expression. In approximately 20% of cases, the underlying cause of Brugada syndrome is a genetic defect in the SCN5A gene, which encodes the sodium channel. Brugada Syndrome manifests with syncope and cardiac arrest, typically occurring in the third and fourth decade of life. The syndrome is characterised by a typical electrocardiogram (ECG) pattern of ST segment elevation in leads V1 to V3, and incomplete or complete right bundle branch block. ICD is indicated in patients with symptoms suggestive of, or evidence of arrhythmias. An Atrial myxoma can present with fevers, raised inflammatory markers and breathlessness worst lying down. There may be embolic causes of CVA or TIA. The murmur could be a diastolic plop or there may be clinical signs similar to mitral stenosis.

Mitral valve prolapse is associated with a risk of endocarditis, atrial septal defect and the long QT syndrome. Squatting increases afterload and this leads to an increase in the intensity of the murmur. Mitral valve prolapse is commonly found in patients with Marfan syndrome, EhlersDanlos syndrome, and adult polycystic kidney disease, and occasionally hypertrophic cardiomyopathy. Carcinoid syndrome. The carcinoid plaque is the characteristic lesion in carcinoid heart disease. Mediator (serotonin, 5-hydroxytryptophan, histamine) release into the hepatic vein from metastatic liver disease predisposes patients to right-sided cardiac lesions. The pulmonary valve shows thickening and retraction. The most important consequence of carcinoid plaques is fibrosis of the valves with resultant distortion of the valvular apparatus and ring. Tricuspid regurgitation and pulmonic stenosis are typically seen. In Ebstein's anomaly, there is congenital malpositioning of the tricuspid valve - the posterior and septal leaflets are displaced into the right ventricular cavity. Tricuspid regurgitation and enlarged right atrium is seen. Ebstein's anomaly is associated with maternal lithium use during pregnancy Flight Rules: A patient should be fit to fly 14 days after an uncomplicated myocardial infarct, after normal activities have been resumed. For complicated MIs, the patient has to wait until symptoms stabilise. Patients are only allowed to fly once resolution of pneumothorax has been demonstrated radiographically and 6 weeks after the event Tricuspid atresia may be defined as congenital absence or agenesis of the tricuspid valve. It is the third most common cyanotic congenital heart defect; the other two more frequently observed cyanotic congenital cardiac anomalies are transposition of the great arteries and tetralogy of Fallot. Tricuspid atresia is the most common cause of cyanosis with left ventricular hypertrophy. Electrocardiographic findings are virtually diagnostic of tricuspid atresia in a young patient with congenital heart disease. The electrocardiogram demonstrates right atrial hypertrophy, an abnormal superiorly oriented major QRS vector, the so-called left axis deviation.

LUNG FUNCTION A decrease in diffusion capacity (DLCO) indicates interstitial lung disease. Forced Expiratory Flow (FEF) 25%-75% primarily reflects the status of the small airways and is more sensitive than the FEV1 for identifying early airway obstruction. It is impaired in bronchiolitis obliterans, smokers, and in patients with lung and heart transplant. Functional residual capacity is measured at the end point of respiration. FRC is raised due to increased air trapping in bronchiectasis. Residual Volume is equal to Total Lung Capacity minus Vital Capacity. Residual Volume is usually 20% of the TLC. Restrictive lung disorders are characterised by reduced FEV1 & FVC, FEV1/FVC >70%, reduced TLC & RV and reduced TLCO. Causes of restrictive lung defect are : - neurogenic or psychogenic causes abnormalities of the thoracic wall - stiff parenchyma (pulmonary fibrosis) - loss of lung tissue, e.g. pneumonectomy - displacement Obstructive lung disorders are characterised by reduced FEV1 & FVC, FEV1/FVC < 70%, raised TLC & RV (gas trapping) and reduced TLCO (emphysema) or normal or raised TLCO (asthmatics). Occupational asthma is defined as asthma induced or aggravated by work. 3-6% of all asthma cases are suspected to be occupational related. The highest groups at risk include: spray painters (isocyanate) plastic makers (resins) farmers (grain dust) bakers (flour) The main objective test in occupational asthma is the two-hourly serial measurement of peak flow for at least two weeks while at work and two weeks while away from work. Full blood count may show eosinophilia. Specific IgE may be raised but it tends to disappear within six months if not exposed to the suspected substance. The British Thoracic Society Asthma guidelines are as follows: Step 1: PRN use of inhaled short-acting beta agonists Step 2: regular inhaled steroids Step 3: high-dose inhaled steroids, or low-dose inhaled steroids plus long-acting beta agonist Step 4: highdose inhaled steroid and regular bronchodilators (sustained release theophylline, inhaled ipatropium, oral long-acting beta agonist, high-dose inhaled bronchodilators, cromoglycate / nedocromil) Step 5: addition of regular steroid tablets Severity of emphysema is defined by the British Thoracic Society (BTS) in relation to FEV1, not FEV1:FVC ratio. Mild is 60-80% predicted; moderate 40-60% and severe <40%. Severe COPD is diagnosed if the FEV1 is less or equal to 30% predicted. In infective exacerbations of COPD, Streptococcus pneumoniae and Haemophilus influenzae, as well as Moraxella are the commonest organisms.

ALVEOLAR DISEASE Extrinsic allergic alveolitis causes a neutrophilia due to cell mediation and eosinophils are normal. Bronchoalveolar lavage shows lymphocytes and mast cells. EAA is a delayed hypersensitivity reaction which may be immune complex (III) mediated or cell mediated (type IV) in chronic disease. Precipitins to micropolyspora faeni in farmers lung or aspergillus are seen. Upper zone fibrosis and crackles can be heard. Symptoms are typically of breathlessness but not wheeze. Extrinsic Allergic Alveolitis is a type III or type IV response. There is no eosinophilia. IgG and lymphocytes are involved in immune response. Antigens of micropolyspora faeni and thermoactinomyces are 0.5-5 microns (not mm). These constitute inhaled antigens which may be detected as precipitins. Haemoptysis is uncommon but can occur. The acute form takes about 6 hours for sensitisation to the inhaled antigen. The chronic form may take weeks. The chronic form is characterized by gradual development of cough, dyspnea, malaise, anorexia, and weight loss. Particle distribution in the lungs parallels the distribution of ventilation; ventilation is greater in the dependent lung bases than in the apices. With chronic exposure, the upper zones are more severely affected. As in extrinsic allergic alveolitis, haemoptysis and wheeze are uncommon in cryptogenic fibrosing alveolitis. Dry cough and breathlessness is common. Rheumatoid factor and anti nuclear antibody may be raised. Neutrophils are raised in CFA, Rheumatoid arthritis and asbestosis. Lymphocytes are raised in granulomatous and drug induced lung disease. CYSTIC FIBROSIS Cystic Fibrosis The abnormality is the chloride transporter, which is encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is cAMP driven. The commonest CFTR gene mutation is due to deletion of 3 base pairs affecting the delta 508 position (phenylalanine) on chromosome 7 (mnemonic : cystic seven). The condition is autosomal recessive. Pulmonary disease develops over a few months after birth. Common infective organisms are pneumoccocus, Haemophilus influenzae and Pseudomonas aeruginosa. Pseudomonas cepacia is rare but major as the infection is serious. Pneumothorax is relatively common over the age of 10 years (5%). Diabetes (20% of patients) occurs due to occlusion and fibrosis of pancreatic ducts. Pancreatic gland occlusion causes malabsorption (diarrhoea). Occlusion of intrahepatic ducts cause cirrhosis and obstruction of bile ducts (pale stools) The sweat test remains the gold standard for confirming the diagnosis of cystic fibrosis. A chloride value of >60 mmol/l is considered positive, between 40 and 60 mmol/l equivocal and less than 40 mmol/l negative. PULMONARY FIBROSIS & BRONCHIECTASIS The causes of upper zone fibrosis in the lung are TB Extrinsic allergic alveolitis ankylosing spondylitis radiation sarcoidosis silicosis Causes of lower zone lung fibrosis are: Asbestosis bronchiectasis cryptogenic fibrosing alveolitis drugs

Drugs which can cause lung fibrosis. Busulphan, bleomycin and methotrexate (cytotoxic agents), Amiodarone, azathioprine, antibiotics (nitrofurantoin, sulfasalazine), penicillamine, gold, phenytoin. The causes of bronchiectasis are: chronic obstruction e.g. tumour Kartagener's syndrome (impaired ciliary motility) cystic fibrosis whooping cough/pertussis tuberculosis smoking

LUNG CARCINOMA The overall survival is 20% and 5 year survival is 6% for all lung cancers. Small cell lung cancer has the worst outcome. Squamous cell carcinoma accounts for approximately one-third of all cases of bronchogenic carcinomas. Unlike adenocarcinoma, it is strongly linked with a history of cigarette smoking. Its histogenesis may be related to chronic inflammation and injury of the bronchial epithelium, which leads to replacement of the normal ciliated columnar epithelium by a squamous epithelium. Squamous cell carcinomas tend to form firm, nonencapsulated, sharply circumscribed masses located in the main, lobar or segmental bronchi. Larger tumors often outgrow their vascular supply and may have central areas of hemorrhage, necrosis or cavitation. SIADH is most comonly seen with small cell carcinoma rather than non-small cell carcinoma. HPOA and hypercalcaemia without bone metastasis is more common in squamous cell carcinoma. Small cell lung cancer has a propensity to spread early. Surgical resection is not a part of the routine treatment. Patients diagnosed following biopsy are treated by combined radiotherapy and chemotherapy. Chemotherapy has been used in non small cell lung cancer but has not been proven to prolong survival (controlled trials). Adverse prognostic factors in small cell lung cancer are: Extensive metastastatic disease weight loss >10% hyponatraemia <132 mmol/l ALP > 1.5 times normal LDH > 1.5 times normal Contraindications for surgical resection of bronchial lung tumour: FEV1 is less than 1.5L Mediastinal LN >1cm Staging >IIIB Nerve involvement is present (rec laryngeal) Malignant pleural effusion is present Malignant mesothelioma is a pleural (not pulmonary) malignancy in which there is almost always a history of asbestos contact. Radiotherapy reduces seeding and invasion through percutaneous biopsy sites. Median survival is approximately 12 months. Pleural fluid provides a diagnosis less than 50% of the time, and even multiple pleural biopsies can be negative in some cases due to a florid fibrotic reaction.

PLEURAL FLUID Causes of transudate are: Congestive heart failure Nephrotic syndrome Cirrhosis Hypoalbuminaemia Urinothorax Peritoneal dialysis Atelectasis (early) Caues of exudate are : Infection (Bacterial, viral, or parasitic) Malignancy Connective tissue disease Chylothorax Pancreatitis Postcardiotomy syndrome Drug-induced (eg, by amiodarone) Esophageal rupture Uremia Subdiaphragmatic abscess Light's criteria (suggests exudate) is satisfied if pleural fluid protein/serum protein ratio greater than 0.5 Pleural fluid lactate dehydrogenase (LDH)/serum LDH ratio greater than 0.6 Pleural fluid LDH greater than two-thirds the upper limit of normal for serum LDH (a cut-off value of 200 IU,/L was used previously) Any pleural effusion associated with bacterial pneumonia, lung abscess or bronchiectasis is a parapneumonic effusion. Streptococcus infection is common. These effusions can be monitored by the pH: pH<7 - absolute indication to insert an intercostal drain pH>7.20 - usually does not need drainage pH 7-7.20 - should be monitored. MISCELLANEOUS Allergic Broncho Pulmonary Aspergillosis: commoner among asthmatics Eosinophilia and high IgE levels are suggestive RAST test for antibodies towards Aspergillus confirms the diagnosis. Acute respiratory distress syndrome is characterised by hypoxaemia, reduced lung compliance, pulmonary hypertension and pulmonary infiltrates on chest X ray. There is damage to the capillary endothelial cell linings resulting in oedema leakage of proteins cells into interstitial alveolar spaces. It is associated with profound hypoxia and increased vascular permeability (causing a V/Q mismatch). A normal PCWP differentiates the condition from pulmonary oedema. It does not respond to steroids. Aspergillomas are masses of fungal mycelia that grow in preexisting lung cavities. Haemoptysis is a common symptom. They do not require treatment with either antifungals or steroids and are not associated with bronchiectasis (unlike allergic bronchopulmonary aspergillosis). Alpha 1 antitrypsin is a glycoprotein synthesized in the liver and comprises 90% of the serum alpha 1 globulin seen on electrophoresis. It is an anti-protease which inhibits neutrophil elastase. The production of alpha1 antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The phenotypes are M, S or Z. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1 antiprotease (serum levels of 20-53 mmol/L). Deficient levels of alpha1 antiprotease are associated with allele Z (MZ or ZZ). Serum levels of the enzyme greater than 11 mmol/L appear to be protective against emphysema. Emphysema develops in most (but not all) individuals with serum levels less than 9 mmol/L.

Byssinosis is caused by cotton dust, and is commoner among smokers. Immunologically, it is different from farmers lung but is more akin to occupational asthma wheeze occurs after exposure to cotton and hemp. The condition typically worse on Mondays when work begins and lung function stabilises throughout the week. The CXR is normal, unlike extrinsic allergic alveolitis, where mottling is seen on CXR (interstitial pneumonitis). Churg-Strauss syndrome (triad of 1) asthma, 2) hypereosinophilia, and 3) necrotizing vasculitis) can present with gastrointestinal involvement may sometimes present as bloody diarrhea or simulating ulcerative colitis and is caused by bowel ischemia. Desquamative interstitial pneumonia (DIP) is a distinct clinical and pathologic entity. It affects cigarette smokers in their 30s or 40s. Most patients present with dyspnea. DIP differs histopathologically from usual interstitial pneumonia (UIP) in that it tends to be diffuse and uniform in appearance. Goodpasture's syndrome is due to the presence of circulating anti-glomerular basement membrane antibodies (anti-GBM antibodies. Hypereosinophilic syndrome is a rare condition where there is an idiopathic eosinophil count of > 15 x 10^9/dl. It generally affects young men ages 20-50. Thrombotic tendency, neurological involvement and restrictive cardiomyopathy occur There is response to steroids. Apart from obesity, obstructive sleep apnoea is associated with acromegaly, hypothyroidism, jaw and craniofacial abnormalities, and alcohol. During the sleep study or polysomnography, a cessation of breathing for 10 seconds with desaturation in oxygen saturation would help to confirm obstructive sleep apnoea. The hallmark clinical symptom of OSA is excessive snoring. Long Term Oxygen Therapy is indicated when pO2 < 8kPa when there is polycythaemia or pulmonary hypertension. In uncomplicated COPD, it is indicated when pO2 < 7.2kPa. Patients without chronic hypoxaemia and not on LTOT, should be considered for ambulatory oxygen therapy if they show evidence of exercise oxygen desaturation (a fall of SaO2 of at least 4% below 90%) Kartagener's syndrome is hereditary. It comprises a triad of: situs inversus (transposition) of the viscera, abnormal frontal sinuses producing sinusitis and bronchiectasis, and immobility of the cilia. Symptoms and signs are dyspnoea, productive cough, recurrent respiratory infections, rheumatoid arthritis, renal abnormalities, malformations of renal vessels and anomalous subclavian artery. There is also otitis media, nasal speech, conductive hearing loss, anosmia or clubbing.

Lofgren's syndrome is a self limiting subset of sarcoidosis. It consists of the triad of fever, bilateral hilar lymphadenopathy and erythema nodosum. Therefore, the prognosis is good and steroids are not required. Legionella pneumophila is an obligate aerobic gram negative bacilli. The natural habitat of the bacterium is water and it is spread through contaminated aerosols. The incubation period is 2-10 days and the spectrum of the disease varies from asymptomatic seroconversion to severe life-threatening pneumonia. Symptoms such as headache, fever, rigors, myalgias and lethargy are frequent. Erythromycin or doxycycline are the drugs of choice and treatment should be continued for at least 3 weeks. Rifampicin (600mg) should be added to the treatment in patients who are severely ill or who have cavitation. Mycobacterium avium complex (MAC) is a saprophyte which is found in soil, water, dust etc. It typically affects middle age and old men with underlying lung diseases such as COPD, old TB, bronchiectasis. It is associated radiographic evidence of disease (cavities etc), and diagnosis should be made after isolation in three sputum samples. Extrapulmonary disease is seen typically in immunosupressed patients. Recommended treatment is with rifampicin and ethambutol for 24 months. Mycoplasma pneumonia is the commonest atypical pneumonia. Approximately 15% of pneumonias in adults are due to Mycoplasma pneumoniae. Transmission occurs from person to person by infected droplets. The incubation period is 9-21 days. The incidence is higher during the winter months. Fever, chills, cough and headache are early symptoms. Dyspnoea, chest pain and haemoptysis are rare. Small pleural effusions may occur but are rare. Cold agglutinins are usually present in a titre greater than 1:32. The acute mortality in pneumocystis pneumonia is usually 10%. Dry cough, fever and tachypnoea are typical in PCP. The organism lies in the alveolar space (foam), causing hypoxia and a low transfer factor. Typically there are no crackles, although it may occasionally be present. The duration of treatment recommended for patients with AIDS is 21 days. Non-AIDS patients with PCP generally respond to therapy within four to five days. Primary pulmonary hypertension presents mostly after age 30s, and more commonly affects women. There is right heart failure and treatment includes prostaglandin analogues (iloprost, epoprostenerol), sildenafil, bosentan and calcium channel blockers. Psittacosis is a systemic illness with primarily pulmonary manifestations. The diagnosis is suggested by exposure to birds. The rash (Horder's spots) and splenomegaly are characteristic. Diagnosis can be made by a four-fold increase in the complement-fixing antibodies. Tetracycline for 2 weeks is the treatment of choice. Causes of phrenic nerve palsy are: pneumonia pleurisy aortic aneurysm substernal goiter neoplasms thoracic surgery herpes zoster infection vasculitis diabetes A protein of >35 g/L suggests an exudate.

Sarcoidosis can cause many changes on the CXR: unilateral or bilateral hilar lymphadenopathy diffuse parenchymal changes eggshell calcification pleural effusions nodules A prolonged history of epistaxis and sinusitis is commonly found in Wegener's granulomatosis. Breathlessness with a raised KCO suggestive of alveolar haemorrhage Causes of pulmonary haemorrhage and renal failure include Wegener's granulomatosis, microscopic polyangiitis and systemic lupus erythematous (SLE).

UPPER GI DISORDERS Achalasia: Botulinum injections are most effective of all the options for relieving a lower oesophageal sphincter restriction which leads to achalasia. Nifedipine, nitrates or sildenafil can also be used, but are less effective. Surgically, Heller s oesophageal myotomy is the best treatment option, it can be done via an abdominal incision or laparascopically. BCS is a good mnemonic for Barrett's dysplasia. Barrett's Columnar replaces Squamous in Barretts oesophagus. This is also known as small intestinal (columnar) metaplasia. There is increased risk of oesophageal adenocarcinoma. Nitrates, caffeine and alcohol can help relieve symptoms by relaxing lower oesophageal tone. Not all patients with GORD should undergo an OGD (should be considered if GI bleeding or symptoms of dysphagia occur). Oesophagitis is present in half of GORD patients. Oesophageal manometry or oesophageal motility study measures the strength of the lower oesophageal sphincter. This would rule out achalasia. A Mallory-Weiss tear occurs in the mucous membrane typically in the lower oesophagus. Mallory-Weiss tears are usually caused by forceful or prolonged vomiting or coughing. They may also be caused by epileptic convulsions. The tear may be followed by vomiting bright red blood or by passing blood in the stool. The incidence is 4 in 100,000 people. Achlorhydria (absence of gastric acid secretion) can be caused by immune destruction to the stomach wall, malnutrition and marijuana use. The pentagastrin test is used as a diagnostic aid for evaluation of gastric acid secretory function. HEPATITIS Hepatitis A is a picornavirus. Hepatitis B is a hepadnavirus. Hepatitis C Virus is a flavivirus. It is a single-stranded RNA virus. Hepatitis B A positive anti-HBc (IgM) and HBsAg suggests acute infection. When the infection resolves, HBsAg becomes negative and anti-HBc (IgG) is positive. In patients who have been vaccinated, HBsAg is negative and anti-HBs is positive.

HbcAg is the first detectable antigen in acute infection but is also detectable in chronic infection. HbsAg is detectable in chronic infection. HbsAb is a sign of previous infection or immunisation. HBeAg (not HBcAg) is the best marker of infectivity, and is used as an important criteria for selection of patients who have chronic hepatitis B for interferon (-2B) therapy. HBV DNA and HBeAg levels are measured in response to the therapy and undetectable levels would be considered successful treatment. 10% of patients with hepatitis B develop chronic infection (as compared to hepatitis C where 80% develop chronic infection). 30% of patients with hepatitis C develop hepatocellular carcinoma over 30 years. 20% develop cirrhosis over 20 years. The treatment options are ribavirin or PEG (polyethylene glycolated) interferon. IFN is only effective in clearing the virus in 25% of patients. Meta-analysis of data strongly suggests a two to three-fold enhanced efficacy of interferon-ribavirin combination therapy over interferon monotherapy in all major subgroups of chronic hepatitis C patients. In hepatitis C, response to therapy is determined by normalisation of hepatic transaminases and undetectability of hepatitis C RNA in plasma. Hepatitis D (delta) is a superimposed infection to Hepatitis B. Hepatitis E causes acute illnesses, and does not result in a chronic carrier state. It is usually transmitted in a faeco oral route (similar to hepatitis A). It occurs mostly in developing countries and is widespread in India, Asia, Africa and Central America. Hepatitis G virus or GBV-C does not appear to cause progressive liver disease. Autoimmune hepatitis occurs in younger to middle aged women. 25% present as acute hepatitis, but the onset is usually insidious. Amenorrhoea is relatively common. It is associated with hyperglobulinaemia rather than hypoglobulinaemia. 60% are associated HLAB8, DR3 and DW3. The sicca syndrome (xerostomia/dry eyes, keratoconjunctivitis sicca) may occur. LIVER DISEASE In hemochromatosis, the commonest mutation is C282Y. It is found in approximately 90% of cases. The mutation is on chromosome 6, affecting the HFE gene. There is an increased incidence in males. The serum Fe is elevated (> 300 mg/dL). The serum transferrin saturation is a sensitive parameter of increased Fe and merits evaluation when > 50%. The serum ferritin is increased ferritin of >1000 mol/l is suggestive (normal <200). Urinary Fe excretion is markedly increased (> 2 mg/24 h) by the chelating drug deferoxamine (500 to 1000 mg IM based on the size of the patient), and this has been used as a diagnostic test. In addition, when the Fe content in the liver is significantly increased, an MRI may reflect this change. Liver biopsy had been the gold standard in diagnosis; it now serves only to provide evidence of fibrosis (cirrhosis). Gene assay (Homozygosity C282y mutations) is the also an excellent diagnostic test.

Venesection is preferred therapy . Treatment consists of bi-weekly venesection removing approximately 500 ml per week. Desferrioxamine infusion (another iron chelator) can also be used. Iron infiltrates the parathyroid glands and can cause hypoparathyroidism. In haemochromatosis , joint deposition of iron occurs, causing arthropathy. Increased iron deposition in the skin stimulates increased melanin production. Haemochromatosis is a recognised cause of restrictive cardiomyopathy. Cardiac damage is commonly seen with ferritin >2,000 ng/l. Wilson disease : The abnormal gene is the ATP7B gene on chromosome 13. It is autosomal recessive. Kayser-Fleischer rings are often seen on slit lamp, but not always. The best test is hepatic copper concentration (> 250 g /g of dry weight). . Typically there is low serum copper levels but high urine excretion of copper. There is low liver production of caeruloplasmin (< 20 mg/dl) in 95% of patients. Copper deposits can occur in the liver and kidney, hence affecting vitamin D metabolism leading to osteomalacia/osteopenic changes. Non-alcoholic steatohepatitis (NASH) is a form of liver disease resembling alcoholic liver disease in a patient who does not consume significant amounts of alcohol. The natural course is relatively benign, but liver cirrhosis. together with all its sequelae, may develop; sometimes liver transplantation is indicated. NASH is associated increased prevalence of Insulin resistance/type 2 diabetes. There may also be lipid abnormalities and increased iron stores. Abdominal tenderness is found in more than 50% of patients with Spontaneous Bacterial Peritonitis. Findings on the abdominal examination can range from mild tenderness to overt rebound and guarding. Traditionally, three fourths of SBP infections are caused by aerobic gram-negative organisms (50% of these being Escherichia coli), and one fourth of these infections are due to aerobic gram-positive organisms ( streptococcal species). An ascitic fluid neutrophil count of > 250 cells/mL and ascites lactate level of >25 mg/dL are the single best predictors of SBP. A combination of an aminoglycoside and ampicillin or cefotaxime can be used. Budd-Chiari syndrome is thrombosis of the hepatic vein, the major vein that leaves the liver. Most patients have an underlying thrombotic tendency. About 10% have polycythemia vera, and about 10% have been on the OCP. The most common symptoms in Budd-Chiari syndrome are hepatomegaly, abdominal pain, ascites and jaundice. Child's Pugh classification includes bilirubin, prothrombin tine, encephalopathy scores, ascites and albumin to measure the severity of liver disease. Somatostatin its derivative, octreotide, and terlipressin are often used for emergency treatment of bleeding oesophageal varices in patients with cirrhosis of the liver. Beta blockers (nadolol), nitrates, vasopressin analogues and somatostatin analogues can also be used for reducing rebleeding in oesophageal varices.

Wernicke encephalopathy is a neurologic disorder of acute onset caused by a thiamine deficiency. The condition is characterized by ocular abnormalities, ataxia, and a global confusional state. Wernicke encephalopathy results from a deficiency in vitamin B-1 (ie, thiamine). The episode may have been precipitated by intravenous dextrose administration which exhausted his vitamin B reserves. B vitamins should be administered to all alcoholic patients requiring dextrose. The main features of Korsakoffs psychosis is short term memory loss and subsequent compensatory confabulation by patient. Other symptoms may include delirium, anxiety, depression, confusion, delusions and insomnia. The treatment is with intravenous thiamine. Hepatorenal syndrome (HRS) is the development of renal dysfunction in patients with severe liver disease (acute or chronic) in the absence of any other identifiable causes of renal pathology. BOWEL DISEASE Crohn's disease is characterised by transmural inflammation, neutrophil infiltrates, lymphoid aggregates, fissures, preservation of crypt architecture and noncaseating granulomata. Ulcerative colitis is typified by mucosal inflammation, general inflammatory cell infiltration, goblet cell mucus depletion and crypt abscesses. Ulcerative Colitis Apart from episcleritis, UC is also associated with cholangiocarcinoma, amyloidosis, pyoderma gangrenosum, ankylosing spondylitis, sacroiliitis. X RAY changes Loss of haustral pattern, lead pipe, and shortened colon on the X ray, suggests ulcerative colitis. In Crohn's disease, transmural inflammation with formation of fissures, ulcers and granulomata, and cobblestone appearance are seen. Inflammatory conditions (e.g Wilson's disease) and drugs such as methyldopa and isoniazid can precipitate chronic active hepatitis. Coeliac Disease: Folate levels are usually normal but not B12 in coeliac disease (in Crohns both are decreased). Dermatitis herpetiformis manifests as a pruritic rash. It is associated with HLA DQ2 haplotype. Anti-endomysial antibodies may be present. Coeliac disease (gluten sensetive enteropathy) is relatively common in Ireland. Gluten is found in wheat, rye and barley. Biopsy in coeliac disease typically shows: hypertrophied crypts of Lieberkuhn, villus atrophy, degenerate surface epithelial cells, an increase in intraepithelial lymphocytes. Jejunal biopsy demonstrating improvement with a gluten free diet is the best form of diagnosis. There is an increase in gastric and small bowel malignancies.

Dapsone (diaminodiphenyl sulfone) and sulfapyridine are the primary medications used to treat Dermatitis Herpetiformis (DH). Dapsone often is used initially; sulfapyridine is substituted in patients unable to tolerate dapsone. Whipples disease, may be confirmed by small bowel biopsy. This will show large, foamy PAS positive macrophages in the lamina propria. Whipple's disease affects mainly men aged 30 to 60. It is caused by an infection with Trophyrema whippelii. Symptoms of Whipple's disease include diarrhea, inflamed and painful joints, fever, and skin darkening. Severe malabsorption results in weight loss along with fatigue and weakness caused by anemia. Antibiotics such as tetracycline, co-trimoxazole and penicillin can be used for treatment (6-12 months). BILIARY DISORDERS Chlorpromazine, tricyclic antidepressants, azathioprine, augmentin and erythromycin cause cholestatic jaundice and also associated hepatitis. Primary sclerosing cholangitis is usually seen in males. It is typically associated with ulcerative colitis. A positive pANCA can occur. The best investigation to confirm this is ERCP, which will reveal multiple strictures in the biliary system. 10% of patients with PSC will progress towards developing cholangiocarcinoma. There is a cholestatic picture (high alkaline phosphatase) on the liver function tests, but not necessarily high bilirubin. pANCA is positive in about 90% of patients with PSC. Ursodexoycholic acid improves clinical symptoms and reduces biochemical evidence of cholestasis but no effect on morbidity and mortality has been demonstrated Primary biliary cirrhosis is more common in females and is usually associated with raised IgM levels. The diagnostic hallmarks for PBC include a cholestatic serum biochemistry: increased serum cholesterol, a moderate increase in triglyceride, serum lipaemia and reduced HDL levels. Clinical features include: palmar xanthomas; tuberous xanthomas (particularly on extensor surfaces); tendinous xanthomas are rare. Connective tissue disorders such as Sjogren's syndrome and scleroderma are associated. Histology shows white cell damage to the biliary epithelium with non necrotising granuloma formation in the portal triad. Treatment should be ursodeoxycholic acid, and replacement of vitamins A,D, E and K, as well as calcium [risk of osteoporosis]. Ursodeoxycholic acid lowers serum bilirubin and symptoms of itching, and prolongs the progression towards requirement for liver transplantation. Liver transplantation does not cure the condition. Unconjugated hyperbilirubinemia in Gilbert syndrome is due to underactivity of the conjugating enzyme system bilirubin-uridine diphosphate glucuronyl transferase (bilirubin-UGT) which converts bilirubin to a conjugated, water soluble form. Crigler Najjar is a more severe form in which the same enzyme is absent and there is neonatal jaundice due to very high levels of unconjugated hyperbilirubinaemia. DubinJohnson syndrome is asymptomatic mild jaundice due to impaired excretion of

bilirubin. In contrast to Gilbert's syndrome, the hyperbilirubinemia is conjugated and bile appears in the urine. MALT lymphoma is the third most common type of non-Hodgkin lymphoma, although it only accounts for about 7-8% of these tumours. MALT lymphomas have been described at almost all extra-nodal sites, but are most commonly found in the gastrointestinal tract (stomach is the commonest). Low grade gastric MALT tumours which are associated Helicobacter Pylori infection respond in over 80% of cases to helicobacter eradication. A proportion of patients will not respond to eradication therapy alone and will go on to more conventional antilymphoma therapies such as such as cyclophosphamide, chlorambucil, nucleoside analogues, or radiotherapy. PANCREATITIS Coxsackie, mumps, ECHO and hepatitis viruses as well as hypothermia can cause acute pancreatitis. The following are poor prognostic indicators in acute pancreatitis: Calcium < 2.0 (hypocalcaemia rather than hypercalcaemia as a consequence) WCC > 15 Urea >16 ALT >200 PaO2 <8 Age > 55 years Glucose > 10 Chronic Pancreatitis Cullen's sign (periumbilical discolouration) can be present Grey Turner's sign (flank discoloration) can be present Purtscher's retinopathy (ischaemic areas in the retina) can be present lack of digestive enzymes leads to steatorrhoea In chronic pancreatitis, trypsin secretion is reduced. Trypsin is required in the processing of dietary B12 which enables absorption and hence B12 deficiency is the most likely. Causes of a raised amylase are: acute/chronic pancreatitis pancreatic cysts and carcinoma perforated duodenal ulcer ovarian carcinoma ectopic pregnancy gallstones salivary tumour adenitis mumps diabetic ketoacidosis anorexia

MISCELLANEOUS DISEASES Peutz-Jeghers syndrome is an autosomal dominant inherited disorder. The cause of Peutz-Jeghers syndrome appears to be a germline mutation of the STK11 (serine threonine kinase 11) gene in most cases. It is characterized by intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules. A 15-fold elevated relative risk of developing cancer exists in this syndrome over that of the general population. Carcinoid syndrome is diagnosed by raised urinary 5-HT levels. A precursor of 5HT, tryptophan is highly metabolised and consequently niacin deficiency (pellagra) occurs. The three D's dementia, dermatitis (a photosensitive rash) and diarrhoea occur. Gut Hormones Secretin is produced by the jejunum. It relaxes the oesophageal sphincter and also stimulates pancreatic enzyme secretion. Gastrin is secreted by the G cells of gastric antrum. It stimulates parietal cells produce hydrochloric acid. Its production is stimulated by neural reflex pathways and also by direct effect of digested peptides on the G cells. It also stimulates the production of bicarbonate. Vasoactive intestinal peptide (VIP) promotes intestinal water and electrolyte secretion. VIPomas [vasoactive intestinal peptide (VIP)] originate in amine precursor uptake and decarboxylation (APUD) cells of the gastroenteropancreatic endocrine system and in adrenal or extra-adrenal neurogenic sites. Features of VIP syndrome include watery diarrhea, hypochlorhydria, hyperglycemia , hypercalcemia, flushing and hypokalaemia due to diarrhoea. Initial treatment is directed toward correcting volume and electrolyte abnormalities by using potassium chloride and sodium bicarbonate. Octreotide controls diarrhea in 80% of cases. Glucocorticoids reduce symptoms in 50% of patients with VIPoma. Macroglossia can be caused by many rare infiltrative conditions including mucopolysaccharoidosis. TB, thyphoid and rheumatic fever are infections which can lead to macroglossia. Causes of parotid swellings. Viruses include mumps, coxsackie A virus, parainfluenzae virus, CMV and varicella zoster virus, Hypothyroidism. H pylori antigen can be measured from stool and H pylori antibody (serology) from blood. The antibodies can be present for more than six months and hence is not a good indicator of acute infection. COX 2 inhibitors such as celecoxib are used as analgesics instead of NSAIDS in patients who are at high risk of upper GI dyspepsia or ulceration. However, there remains an increased risk of ulceration, though less so compared to NSAIDS.

Misoprostol (prostaglandin analogue) and cimetidine are used in treatment of gastrooesophageal ulceration. COX 2 inhibitors have also recently been shown to increase the mortality rate of patients with coronary artery disease by blocking the antithrombotic effects of certain prostaglandins. The symptoms of fevers, weight loss and lower back pain are classical for retroperitoneal fibrosis. There is an association with inflammatory conditions such as SLE, rheumatoid arthritis, ankylosing spondylitis, Hashimoto's thyroiditis and glomerulonephrosis. CT or MRI shows can fibrotic para-aortic masses causing ureteric obstruction. Drugs associated with retroperitoneal fibrosis include: methysergide beta-adrenergic blockers lysergic acid diethylamide (LSD) methyldopa methysergide amphetamines phenacetin pergolide cocaine Azathioprine is used to treat retroperitoneal fibrosis. Retroperitoneal organs are kidneys, aorta, pancreas ascending colon most of duodenum

ACUTE TUBULAR NECROSIS A rapid rise in creatinine following periods of hypotension is most commonly due to acute tubular necrosis. In ATN, urinalysis usually shows granular casts. Urine sodium is typically high due to tubular sodium loss, concentration is typically above 30 mmol/l. The urine to plasma osmolality ratio <1:1, the ability to concentrate urine is preserved despite sodium loss. Acute Tubular Necrosis is associated with accelerated hypertension, hypotension, diabetes, liver failure, eclampsia, aminoglycosides, Cephalosporins, Cisplatin, Amphotericin and Ciclosporin. Haemodialysis is useful for salicylates and NSAIDs, lithium, and in particular, Antifreeze poisioning. It is not useful for tricyclics, amiodarone and paraquat, paracetamol and digoxin, which is mostly tissue bound (use digoxin binding antibodies). Indications for urgent dialysis are: uraemia pericarditis with effusion pulmonary oedema significant hyperkalaemia (>7) with evidence of ECG changes rapidly rising urea and creatinine In haemodialysis patients, sodium intake has to be moderated - high intake may cause fluid overload. Aluminium levels may accumulate in dialysis patients, so antacids containing aluminium should be avoided. PTH levels are usually high. Continuous Ambulatory Peritoneal Dialysis (CAPD): Recent inguinal hernia surgery and history of perforated diverticular disease are relative contraindications. Large volumes of intraperitoneal fluid may compromise severe COPD. Patients with severe arthritis will not be able to manage peritoneal bag changes. NEPHRITIC AND NEPHROTIC SYNDROME Infectious causes of acute nephritic syndrome are: staphylococcus pneumococcus v chickenpox malaria Non infectious causes acute nephritic syndrome: Membranoproliferative glomerulonephritis IgA nephropathy Henoch-Schnlein purpura systemic lupus erythematosus mixed cryoglobulinemia Goodpasture's syndrome Wegener's granulomatosis

Proteinuria Microalbuminuria is protein >30 mg/l but dipstick testing can detect protein >300mg/l. 2+ proteinuria approximates to 1g/l of prtein. 3+ proteinuria approximates to >3g/l. The diagnosis of nephrotic syndrome comprises the triad of oedema, proteinuria >3g/d and hypoalbuminaemia. Hypercholesterolaemia is present in nearly all patients. Renal vein thrombosis and bacterial infections are also common. Complications of nephrotic syndrome are : hyperlipidaemia hypoalbuminaemia associated hypocalcaemia (Vit D binding protein Vitamin D lost in nephrotic urine) prothrombotic tendency (eg renal vein thrombosis, DVT) congestive cardiac failure pneumococcal pneumonia acute and chronic renal failure GLOMERULONEPHRITIS Granular casts, red cell casts and selective proteinuria suggest glomerulonephritis. Minimal change nephrotic syndrome is responsible for 90% of the cases of nephrotic syndrome in children less than 5 years of age. It also occurs in adults - approx 20%. The name is derived from the fact that the only detectable abnormality histologically is fusion and deformity of the foot processes under the electron microscope. Minimal Change Disease is steroid responsive and in general, does not lead to chronic renal failure. There is response to corticosteroids usually within the first month. 90% of patients with minimal change disease in the younger age group achieve remission after 8 weeks of steroids. Membranous glomerulonephritis / nephropathy is characterised by subepithelial deposits of immune complexes in the glomerular basement membrane. It is a glomerular disease rather than a renal tubular acidosis. It is associated with malignancy (CLL, NHL), connective tissue disease (SLE, RA), infections (Hep B, malaria) and drugs (gold, penicillamine, captopril). Membranous nephropathy is the commonest cause of the nephrotic syndrome in adults, whereas in children it is minimal change disease. The renal biopsy with membranous nephropathy shows a thickened glomerular basement membrane and granular IgG + C3 on immunostaining. Overall, 1/3 rapid decline, 1/3 respond to steroids and chlorambucil, 1/3 remit spontaneously. The goal of treatment is to minimize symptoms and slow the progression of the disease. Often, corticosteroids or immunosuppressive medications may be used to reduce symptoms and progression of the disorder. Note: membranous GN is associated with Non-Hodgkins lymphoma but Hodgkins lymphoma is associated with minimal change GN. Focal Segmental Glomerulonephritis In infective endocarditis, immune complexes form and may lead to Focal segmental proliferative glomerulonephritis. ACE

inhibitors usually reduce proteinuria and lipemia, and may slow the progression towards renal disease. Mesangio Capillary Glomerulonephritis occurs in post streptococcal infection and caused by immune complexes depositing sub endothelially (capillary). The two most common variants are type I MCGN and type II MCGN (also called dense deposit disease). Type I is much more common than type II, which is a rare disease. MCGN is characterized by capillary basement membrane thickening and mesangial cell proliferation. It are associated with low levels of C3. Mesangiocapillary glomerulonephritis is a significant cause of nephrotic syndrome in children (accounts for about 8% of cases) and adults (accounts for about 14%). Immune complex deposition is predisposed to by C3 nephritic factor rise in MCGN type II, which stabilises C3bBb and activates the complement pathway. In post streptococcal glomerulonephiritis, oliguria, proteinuria and haematuria occurs. Diffuse proliferative glomerulonephritis is the commonest glomerulonephritis in SLE. There is mesangial and endothelial cell proliferation, polymorphonuclear cell infiltrate and granular subepithelial deposits of C3. It also carries the worst prognosis with progression towards renal failure. The currently recommended therapy is pulse intravenous corticosteroids in combination with pulse cyclophosphamide continued for at least 12 months after remission. Newer regimes include combinations of prednisolone and mycophenolate RENAL TUBULAR ACIDOSIS Urine pH is determined by H+ concentration. Urine is more alkalotic on a vegetarian diet. In type I RTA, the ability to develop a hydrogen ion gradient across the distal nephron is impaired so that the urine pH is never < 5.5. In Renal Tubular Acidosis , the defect is in excretion of acid in Type I RTA and absorption of bicarbonate in Type II. Nephrocalcinosis occurs in type I distal RTA due to less acid urine acidification of urine is more difficult in type I. Inability to reduce the urinary pH below 5.4 is typical of Type I RTA. In contrast, phosphate handling is worse in type II proximal RTA e.g. Fanconi syndrome (phosphaturia, aminoaciduria, glycosuria) and osteomalacia occurs. Hypokalaemia is a feature of renal tubular acidosis. Bicarbonate wasting in the proximal tubules is the primary problem. Expired tetracycline use is a cause of proximal type II RTA. RENAL STONES Calcium oxalate and urate stones are a common association with bowel resection due to hyperabsorption of oxalate and concentrated urine. Calcium oxalate stones are the commonest kind of stones. Calcium phosphate stones are the second commonenst and account for 20%. Uric acid stones (5% of all stones) are associated with high purine metabolism, chronic diarrhoea, gout.

Cystinuria is a disorder of proximal tubular cells. Amino aciduria (COAL cystine, ornithine, arginine, lysine) causes cystine stones (accounts for 1% of all stones). Proteus splits urea into ammonia, causing alkaline urine. They predispose to struvite stones (magnesium ammonium phosphate). Radiopaque stones are: Calcium oxalate, calcium phosphate, triple phosphate, cystine stones. Radiolucent stones are: Uric acid, xanthine stones. MISCELLANEOUS IgA nephropathy or Berger's disease is a clinical/pathological entity defined by the presence of macroscopic or microscopic hematuria and mesangial IgA deposits. Signs and symptoms include proteinuria, nephrotic syndrome, acute nephritis, malignant hypertension, chronic renal failure, and acute renal failure. Proteinuria is typically within the mild range. There is a 2:1 male predominance. Findings on renal biopsy are characteristic. In all patients, IgA is present and is deposited mainly in the mesangium of the glomerular tuft. Other immunoglobulins and complement, especially C3, are often found in a mesangial pattern. Although there is no cure, progression towards ESRF occurs usually in about 10-20 years, quicker if hypertension were present (which should be treated with an ACE inhibitor). Analgesic nephropathy is usually a result of prolonged or chronic ingestion of analgesics, especially over-the-counter (OTC) medications that contain phenacetin or acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin or ibuprofen. The ingestion may have been excessive over a period of years. This frequently occurs as a result of self-medication, often for some type of chronic pain. There is interstitial nephritis and renal papillary necrosis, eventually leading to acute renal failure or chronic renal failure. There may be haematuria but minimal or no proteinuria. Adult Polycystic Kidney Disease : Inheritance is autosomal dominant. There is a mutation on the short arm of chromosome 16 (there are 16 alphabets in polycystic kidney). Genetic linkage analysis can be done as well (but less practical) to screen for PKD1 mutation on chromosome 16 and a PKD2 mutation on chromosome 4. 5% of patients with APKD have intracranial aneurysms and 20% have mitral valve prolapse, and even abdominal hernias. Pancreatic cysts occur in 10% of patients. Ultrasonography with the criteria of more than 2 cysts in < 30 years age group is diagnostic of adult polycystic kidney disease. Flank pain and haematuria occur and there is increased risk of infections. Cysts form primarily from collecting ducts. About 50% of patents reach end stage renal failure at age 50. Amyloid : Nephrotic syndrome and renal vein thrombosis can occur in amyloid renal disease. Congo red staining shows apple green birefringence with polarised light in amyloidosis. AL amyloid may respond to cytotoxic therapy and resolution of proteinuria may occur.

Alport syndrome encompasses a group of heterogeneous inherited disorders involving the basement membranes of the kidney and frequently involving the cochlea (nerve deafness) and the eye (visual disturbance). Inheritance can be autosomal dominant, recessive or X linked recessive. These disorders are the result of mutations in type IV collagen genes. Gross haematuria is the commonest presentation, along with visual disturbance and deafness. Renal impairment and nephrotic syndrome may develop later in life Bartters syndrome is hypokalaemic alkalosis due to hyperaldosteronism. The defect is due to reduced resistance to angiotensin II. Liddles syndrome is a rare condition in which there is hypokalaemic alkalosis but low aldosterone levels are found. It is seldom necessary to treat metabolic alkalosis by acidification, fluids often help to correct it. Causes of nephrogenic Diabetes Insipidus are- hypercalcaemia hypokalaemia sickle cell disease lithium carbonate amyloidosis myeloma malnutrition analgesic nephropathy pregnancy demeclocycline methicillin Diabetic nephropathy In type I diabetes, there is a 50% chance of progressing towards ESRD. In type II diabetics, there is a 15% chance of doing so. Familial hypocalcuric hypercalcaemia (FHH) due to a mutation in the calcium receptor. Familial hypocalciuric hypercalcemia (FHH) or familial benign hypercalcemia is an autosomal dominant inherited disorder of calcium metabolism. It is characterized by lifelong asymptomatic hypercalcemia associated with a relative hypocalciuria and a tendency to hypermagnesemia. The biochemical features of this disorder are difficult to distinguish from mild primary hyperparathyroidism. Several patients have had parathyroidectomy for hyperparathyroidism with no effect on calcium levels. Henoch Schonlein purpura (HSP) causes a rash around the trunk and polyarthritis. It is associated with renal failure caused by a glomerulonephritis which is similar to Ig A glomerulonephritis causing macroscopic haematuria. Multiple myeloma: Proteinuria is present in 90% of patients and abnormal light chains (Bence Jones protein) are found in 80% of patients. At diagnosis, the creatinine level is elevated in 50% of patients. Proximal tubules are increasingly damaged by the large protein load, and large obstructing casts frequently form within the tubules. The combination of interstitial fibrosis and hyaline casts surrounded by epithelial cells or multinucleate giant cells constitutes myeloma kidney.

Additionally, hypercalcemia and hypercalciuria as well as hyperuricemia contribute to kidney damage. Renal amyloidosis (usually lambda light chains) and light chain deposition disease (usually kappa light chains) occurs. Cryoglobulinaemia is uncommon but may cause a membranoproliferative glomerulonephritis Sarcoidosis : Renal involvement occurs infrequently in children and adults with sarcoidosis. Renal disease can be attributed to granulomatous interstitial infiltration or to disorders of calcium homeostasis, including hypercalcemia and hypercalciuria with or without nephrocalcinosis and nephrolithiasis. Clinically, variable renal disease occurs in 5-10% of adult cases. The clinical manifestations in reported cases of renal granulomatous sarcoidosis include proteinuria, leukocyturia, hematuria, concentration defect, hypertension, and renal failure. von Hippel Lindau disease is transmitted as an autosomal dominant condition. Affected individuals may have renal cysts, Clear cell renal cell carcinoma (CCRCC), retinal angiomas, central nervous system haemangioblastoma, phaeochromocytoma. Wegener's granulomatosis: Sinusitis can arise from involvement of the nasal tract and sinuses in the Wegener's pattern of the disease. Often a patient with systemic vasculitis will have a long history of indolent disease, but will then present late with severe aggressive disease. Serum anti-neutrophil cytoplasmic antibodies (ANCA) and antibodies against the ANCA antigens myeloperoxidase and proteinase 3 may be positive. Renal vein thrombosis can present with nephrotic syndrome, haematuria, loin pain and worsening renal failure. Treatment is with heparin/warfarin. Rhabdomyolyis causes myoglobinuria, which must be differentiated from haematuria. Causes of rhabdomyolysis are falls, drugs (metals, gasoline, alcohol), viral infections & malaria.rhabdomyolyis causes myoglobinuria, which must be differentiated from haematuria. Ultrasound is a good method of detecting renal scars. DMSA, which is taken up by tubular cells can be used to detect scars (as opposed to DTPA which is filtered by the glomerulus and not taken up by tubular cells, hence not good for detecting scarring).

PITUITARY DISORDERS Growth Hormone usually decreases following an elevation in blood glucose after a meal. It is usually increased during sleep or during starvation. It causes both retention of sodium and potassium which are required for growth metabolism. Elevated GH levels increase IGF-1 blood levels. Because IGF-1 levels are much more stable over the course of the day, they are often a more practical and reliable measure than GH levels. Elevated IGF-1 levels almost always indicate acromegaly. The oral glucose tolerance test is also used to diagnose acromegaly, because ingestion of 75 g of the sugar glucose lowers blood GH levels less than 2 ng/ml in healthy people. In patients with acromegaly, this reduction does not occur. In acromegaly, hypertension, diabetes and goitre are associated. A damaged pituitary stalk reducing the dopamine suppression signal, stimulates prolactin secretion. Pseudogout (calcium pyrophosphate deposition) is also associated. Patients have normal calcium but increased phosphate levels. Patients with acromegaly have an increased risk of colorectal neoplasia. The best treatment option for a large pituitary tumour in acromegaly is transphenoidal removal of the tumour. Octreotide (somatostatin analogue) and pegvisomant (growth hormone receptor blocker) are effective forms of treatment. Bromocriptine (dopamine agonist) is less effective. Prolactin secretion is inhibited by dopaminergic pathway. Hyperprolactinaemia can be caused by Dopamine receptor antagonists (many antipsychotic drugs e.g. phenothiazines, risperidone), hypothyroidism, liver or renal failure, pituitary adenoma /acromegaly. It leads to galactorrhoea and osteoporosis/osteopenia. Treatment is with dopamine receptor agonists (bromocriptine, cabergoline). Microprolactinoma: The most frequent symptoms at onset are oligoamenorrhoea (60%) and galactorrhoea (50%), and headaches. Treatment is with bromocriptine (e.g. 5 mg od). Cushing's syndrome is a non-specific name for any source of excessive glucorticoids. There are four main causes: 1) Exogenous glucocorticoids 2) Pituitary Cushings syndrome known as Cushings disease, due to a pituitary adenoma secreting excessive ACTH 3) Ectopic production of ACTH. Two varieties; one due to malignant tumours usually of the lung , these patients present with hypertension, hypokalaemia and hyperpigmentation. The second type is due to carcinoid tumours. In the dexamethasone suppression test normal individuals suppress cortisol levels to < 50 nmol/L.

The inferior petrosal sinus sampling test, an elevated central ACTH concentration compared to a peripheral value (from arm veins) indicates pituitary dependent Cushing's disease. The test involves a microcatheter being advanced through initially the femoral vein and eventually into the inferior petrosal sinuses which lie along the internal aspect of the skull base which drain blood from the pituitary gland. Metyrapone is an inhibitor of 11 beta hydroxylase, inhibiting the conversion of 11 deoxycortisol to cortisol, and can be used as treatment in Cushings syndrome. In ectopic ACTH syndrome, hypokalaemic alkalosis is typical. Ectopic ACTH is not suppressed by high doses of steroids such as 8 mg dexamethasome. It is typically caused by small cell carcinoma of the lung. Thymoma, carcinoid tumour, medullary carcinoma of the thyroid, pancreatic carcinoma and phaeochromocytoma are associated with ectopic ACTH secretion. Pituitary apoplexy is characterized by sudden onset of headache, visual symptoms, confusion and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland. The pituitary gland is susceptible to infarction during pregnancy due to its increased size/blood flow. Hyponatraemia, hyperkalaemia and hypoglycaemia are as a result of secondary adrenal failure due to lack of ACTH. Clomiphene is used as a fertility drug in hypopituitarism. It stimulates ovulation through the release of gonadotropins from the pituitary gland. It can also be used in PCOS and in treating male infertility. DIABETES A random glucose of >11.1 and a fasting glucose of >6.8 mmol/L (two occasions) would confirm the diagnosis . Diabetic neuropathy Autonomic neuropathy to the gut, bladder and sexual organs (impotence) can occur. A 3rd nerve mononeuropathy can occur. Motor neuropathy can cause muscle wasting, and sensory neuropathy causes vibration sensory loss. In diabetic patients with microalbuminaemia demonstrated on urine dipstick, ACE inhibitors have been shown to reduce progression towards diabetic nephropathy. Aggressive hypertension control is the best way of preventing progression from microalbuminuria to macroalbuminuria. Although glycaemic control is important, it is not as important as hypertensive control in preventing progression towards nephropathy. According to NICE guidelines, target of HbA1c is 6.5-7.5%, BP target is 135/75, albumin:creatinine target is ratio >2.5 (men) and >3.5 (women), renal consult advised if creat >150, and ACE inhibitor should be introduced to those with microalbuminuria.

In diabetics who have had an MI, the DIGAMI study showed that intravenous insulin for 24 hours and subcutaneous insulin for 3 months improved mortality rates for up to 3 years after. Metformin is a biguanide. It improves insulin sensitivity and is helpful especially in patients who are overweight as it does not stimulate appetites in the way that sulphonylureas do. Hyperosmolar non ketotic coma is characterised by markedly raised blood sugar, often >50 mmol/L. There is no significant ketosis and acidosis. It occurs in patients with Type 2 diabetes of middle age or older. Treatment should be with isotonic saline , low dose insulin and potassium replacement. Syndrome X describes a range of abnormalities often seen with insulin resistance. These include hyperinsulinaemia, hypertension, hypertriglycerides, low HDL and obesity. THYROID DISORDERS Clinical features of hypothyroidism are cold intolerance, constipation, menorrhagia, angina, myxoedematous facies, dry rough skin due to mucopolysaccharoidoses, hair loss, hoarse voice, dementia, cerebellar ataxia, peripheral neuropathy and depressed reflexes. Recognised features of thyrotoxicosis are: Weight loss, Palpitations, Dyspnoea, Irritability, Psychosis, Tremor, Pruritus, Diarrhoea, Palmar erythema, Hypercalcaemia, Hyper-reflexia, Bone mineral loss and Alopecia. Graves disease is the diagnosis - thyroid autoantibodies are increased. Almost 80% of patients have exopthalmos. Medical treatment such as carbimazole or radioiodine treatment are recommended rather than surgery. There will be increased uptake on the thyroid radioisotope scan. Toxic thyroid nodules are best treated with radioactive iodine as this concentrates on the overactive adenoma cells. Radioiodine treatment is contraindicated in young children, pregnant and lactating women. The major complication of treatment with radioactive iodine is the progressive incidence of hypothyroidism and thyroid replacement may be necessary in the future. The appropriate initial treatment of Amiodarone induced hyperthyroidism would be carbimazole +/- steroids. Subacute thyroiditis (De Quervains thyroiditis) is a transient thyroditis which is thought to be of viral aetiology. There is a swollen painful thyroid gland with hyperthyroidism. This is usually followed by a period of hypothyroidism with raised TSH weeks later. Antithyroid medication is not effective. Steroids can be used in severe cases.

Hashimotos thyroiditis. This disorder occurs most commonly in middle-aged women and is caused by the reaction of the immune system against the thyroid gland. It may occur in people with a family history of thyroid diseases or with other autoimmune diseases, especially type 1 diabetes or adrenal insufficiency. Sick euthyroid is seen in unwell patients who are clinically euthyroid but have low levels of T3 and T4. The syndrome is very common and, in fact, may be found in up to 70% of hospitalized patients. This is often why TFTs are not accurate on patients in ITU. The rare syndrome of resistance to thyroid hormone (RTH) is an inherited disorder called Refetoff syndrome that involves reduced tissue sensitivity to the thyroid hormone. Calcitonin is secreted by thyroid cells. Its release is stimulated by a high calcium level. Bone cells lay down calcium in response to calcitonin, and hence it is used as a treatment for osteoporosis. Calcitonin also stimulates renal excretion of calcium. THYROID CARCINOMA Medullary thyroid carcinoma produces peptides and neurohormones which lead to symptoms of irritability, diarrhoea and sweating. It can be inherited in association with MEN type II. Anaplastic thyroid carcinoma is commoner in female patients. It can present with dysphagia, cough and neck pain. It is more invasive than papillary carcinoma. Poor prognostic factors in thyroid carcinoma include advanced age (>50), male, advanced stage, prior neck surgery, and associated multiple endocrine neoplasia. Overall, papillary carcinoma has a 30-year cancer-related death rate of 6%. Follicular carcinoma has a 30-year cancer-related death rate of 15%. PARATHYROID DISORDERS Parathyroid hormone levels rise with hypocalcaemia. It increases plasma calcium by: increasing osteoclastic resorption of bone (rapid effect) increasing intestinal absorption of calcium (slow effect) an increase in tubular resorption of calcium and increased excretion of phosphate Primary hyperparathyroidism. The radiograph of the skull commonly shows osteopenia with a speckled appearance - the so called "pepper pot skull". In primary hyperparathyroidism, typically there is hypercalcaemia, low phosphate and raised alkaline phosphatase. Causes of hyperparathyroidism are: 1.Diffuse hyperplasia 10-40% 2.Single adenoma 5080% 3.Multiple adenomas 10%. 4.Parathyroid Carcinoma 2%

Pseudohypoparathyroidism is a genetic disorder that resembles hypoparathyroidism (lowered levels of parathyroid hormone) but is caused by a lack of response to parathyroid hormone rather than a deficiency in the hormone itself. A picture very similar to hypoparathyroidism develops with hypocalcaemia in the blood and high phophate levels. This defect also causes short stature, round face and short hand bones and is also called Albright's hereditary osteodystrophy. When Albright's hereditary osteodystrophy occurs without hypocalcemia, it is known as pseudopseudohypoparathyroidism. DiGeorge syndrome is a cause of hypoparathyroidism. The disorder is associated with thymic aplasia, immune deficiency and cardiac anomalies (tetralogy of Fallot VSD, ASD). MULTIPLE ENDOCRINE DISORDERS MEN 1 [pituitary tumour, parathyroid hyperplasia/tumour, pancreatic tumours (most commonly gastrinoma / insulinoma)]. Also known as Wermers syndrome. Hyperparathyroidism is the most common and earliest feature of MEN1 ( 80-95%). Usually all four glands become hyperplastic. Neoplastic transformation of pancreatic islets is the second most common manifestation of MEN1 (80%). Gastrinomas are the most common (presenting with peptic ulcer disease and diarrhoea. Insulinomas are the second most common. Pituitary tumours occur in 50-70% of cases. Familial multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder. The MEN1 gene on chromosome 11q13 has been cloned and mutations identified. The gene emcodes a protein called menin which acts as a tumour suppressor gene. MEN 2 MEN 2a is associated with medullary thyroid carcinoma (MTC), parathyroid tumours (10-20%) and pheochromocytoma (20-50%). MEN 2b is associated with presentation of medullary thyroid carcinoma, parathyroid tumours and pheochromocytoma + ganglioneuromatosis (pathognomonic), and marfanoid habitus. ADRENAL DISEASES Insulinoma: Hypoglycaemic attacks are likely to be witnessed during a 72 hour fast which is used to make the diagnosis. Insulin and C peptide levels are high, whilst glucose is low. In Conn's syndrome, renin levels are low, and excretion of potassium is high due to increased sodium retention. There is autonomous aldosterone secretion in the presence of low or suppressed renin activity. A low potassium (< 3.5 mmol/L) accompanied by metabolic alkalosis is characteristic.

Adrenal adenoma is the commonest cause of Conn's syndrome. Sodium chloride infusion is a diagnostic test, aldosterone levels are suppressed in the normal population but not in Conn's syndrome patients. Autoantibodies against 21-hydroxylase (P450c21) are common in Addison's disease. Granulomatous, lymphocytic inflammation of adrenal glands occurs in autoimmune adrenalitis. There is also a genetic predisposition in those with HLA-B8, HLA-DR3, HLA-DR4 haplotypes. Addisons disease as suggested by hyperpigmentation, hyponatraemia and hypotension. A high 9 am plasma ACTH level with low or normal cortisol will confirm the diagnosis of primary hypoadrenalism. A low cortisol response with the short ACTH (synacthen) test would also show that the adrenal gland is not responding to ACTH. Associations with Addisons disease: pernicious anaemia primary ovarian failure vitiligo diabetes The short synacthen test is done via the following: 1) take a basal sample for cortisol at time 0 min. 2) give 250 microgramme Synacthen i.v. or i.m. 3) sample for cortisol are taken at 30 mins. There should be a significant response unless the patient is addisonian. Steroid replacement is usually given 10/5/5 mg or 10/5 mg, although this is adjusted with cortisol day curves. Fludrocortisone 100 g mane should be adequate. Steroids: The equivalent ratio of prednisolone: hydrocortisone is 1:4. The ratio for dexamethasone : prednisolone is 1:10. The ratio for dexamethasone: hydrocortisone is 1:40. Waterhouse-Friderichson syndrome is due to meningococcal septicaemia resulting in adrenal haemorrhagic insufficiency. Symptoms and signs include hypotension, abdominal pain, hyponatremia. The progression is rapid. There may also be disseminated intravascular coagulation in patients with this syndrome. If this condition is not treated promptly then mortality approaches 100%. The treatment is as that for meningococcal infection, but with the addition of adrenal support with hydrocortisone, given intravenously in a dose of 200 mg per four hours. Kallman's syndrome describes the occurrence of hypothalamic gonadotrophin releasing hormone deficiency and deficient olfactory sense - anosmia. It is usually inherited as an X-linked or autosomal recessive disorder with greater penetrance in the male. More than half of patients have associated nerve deafness, colour blindness,

mid-line cranio-facial deformities such as cleft palate or harelip, and renal abnormalities. Most are of normal or above average stature. Females may present with primary amenorrhoea; males with cryptorchidism. LH and FSH levels are typically low. Klinefelter's syndrome is the most common cause of male hypogonadism with an incidence of 1 in 1000 male births. Individuals have an extra X chromosome. Usually, the karyotype is 47, XXY. Accelerated atrophy of germ cells before puberty results in sterility with small, firm testes. Many patients are tall with relatively long legs. Behavioural disorders and delayed speech development are common. Testosterone therapy may be used to improve the development of secondary sexual characteristics. Testicular feminisation is a cause of primary amenorrhoea rather than secondary amenorrhoea. Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. Most patients with complete androgen insensitivity have a female gender. Some patients are first seen in the teenage years for evaluation of primary amenorrhea, but most are identified in the newborn period by the presence of inguinal masses, which later are identified as testes during surgery. Vasopressin (Anti Diuretic Hormone) acts on the distal tubule and collecting ducts to increase permeability to free water. Deficiency of this hormone in diabetes insipidus results in the excretion of dilute urine (increased water clearance) and hypernatraemia. In a normal response to the water deprivation test the maximum urine osmolality exceeds plasma osmolality and the urine osmolality does not increase > 5 % after administration of vasopressin. The plasma osmolality normal range is 278-300 mosmol/kg and urine osmolality normal range is 350-1000 mosmol/kg. In diabetes insipidus, patients are unable to concentrate their urine to greater than plasma osmolality but after administration of vasopressin the urine osmolality increases by > 50 %. Patients with nephrogenic diabetes insipidus are unable to concentrate their urine and they show no response to vasopressin In psychogenic diabetes insipidus or compulsive water drinking, fluid deprivation would stop the polyuria. Plasma and urine osmolality (<300 msom/kg) should be low in psychogenic diabetes insipidus. SIADH is confirmed by inappropriately elevated urine osmolality (often above 300 mOsm/kg) and urine sodium concentration (usually above 40 mEq/liter). Phaeochromocytoma is a tumour of the adrenal medulla. The adrenal cortex produces aldosterone, cortisol (glucocorticoid) and adrenal androgens. The medulla produces adrenaline and noradrenaline. Phaeochromocytoma is associated with MEN II and von Hippel Lindau syndrome. There is an association with retinal, cerebral and

renal haemangiomas. Diagnosis is with raised urinary catecholamines over 24 hours, and also MIBG scan of the adrenals. The treatment of hypertension in phaeochromocytoma is with alpha blockade prior to beta blockade. Alpha blockade reverses the peripheral vasoconstriction whereas beta blockade prevents tachycardia. The preferred alpha-blocker phenoxybenzamine, as it is not a selective alpha 1 blocker but an irreversible alpha-blocker whose effects cannot be overcome by an increase of catecholamines. Hypertension should be managed with phenoxybenzamine initially, increasing up to 80 mg per day, with addition of propanolol after 3-4 days of alpha blockade. Surgery without adequate alpha and beta blockade can result in hypertensive crisis (leading to high CVA, MI complications). Polycystic Ovarian Syndrome (PCOS) is characterized by irregular ovulation and menses, obesity, insulin resistance, acne, and hirsutism (excessive hair growth). Impaired fertility is a prominent feature of PCOS. This is believed to result from elevated insulin levels that stimulate excess androgen production by the ovaries. Biochemically, PCOS is associated with: a raised LH:FSH ratio insulin resistance hyperandrogenism (raised androstenedione levels and raised testosterone). Rapid development of hirsutism is usually caused by an adrenal tumour. There are high testosterone or DHEA levels in the plasma. Causes of hirsutism include: cyclosporin A Risperidone Minoxidil Phenytoin Ovarian tumours Polycystic Ovary syndrome Congenital adrenal hyperplasia Alopecia is associated with SLE hypopituitarism zinc and iron deficiency hyper and hypothyroidism Hyperpigmentation is associated with pellagra porphyria cutanea tarda Nelson's syndrome Haemochromatosis Addison's disease Whipple's disease primary biliary cirrhosis.

Congenital adrenal hyperplasia: Hirsutism, ambibuous genitalia and precocious puberty in boys (normal puberty is seen in girls). Premature epiphyseal closure is a classical feature of CAH. It is also associated with hyperpigmentation and hyperreninaemia due to sodium loss and hypovolaemia. 21-hydroxylase deficiency is the commonest cause of congenital adrenal hyperplasia. This leads to excess androgen production due to shunting of 17 OH progesterone into testosterone and androstenedione production. Increased 17 (OH) progesterone or pregnanetriol in the urine is diagnostic of 21 hydroxylase deficiency. Virilisation may result in clitoromegaly and labial fusion in the female at birth. 11-beta-hydroxylase is the second most common variant of CAH and accounts for approximately 5% of cases. Deficiency of 11 beta-hydroxylase results in a loss of cortisol; hence, due to feedback mechanisms, there is an increase in ACTH and a subsequent increase in production of 11-deoxycorticosterone. Diagnosis is made by measuring 11-deoxycortisol, which is typically high. In the classic form, other hormones that may be elevated include DOC (a potent mineralocorticoid), urinary 17-ketosteroids, and urinary tetra hydrometabolites. Congenital Adrenal Hyperplasia : There is also cortisol deficiency and replacement with dexamethasone or hydrocortisone is appropriate. Efficacy of treatment is best monitored by 17OH progesterone and androstenedione levels. Renin activity levels can be used monitor adequacy of mineralocorticoid replacement. Hypertension and hypokalaemia suggest excess treatment. Alkaptonuria is an autosomal recessive disease due to deficiency of the homogentisate oxidase enzyme. It causes accumulation of homogentisic acid which deposits in cartilage and connective tissue (causing sacroiliac joint and knee pains). It is one of the causes of pseudogout. Oxidation of homogentisate causes urine to turn dark on standing. Familial hypocalciuric hypercalcaemia is an autosomal dominant disease. The pathophysiology is due to a defective calcium receptor on the membranes of the parathyroid and renal tubular cells. This results in a decreased renal clearance of calcium, PTH is usually normal or increased, PO4 is usually decreased. Diagnosis is made on family history and determination of low urinary calcium clearance. Typically, the Fractional Excretion of Ca is <1%. Haematin causes suppression of -aminolaevulinic acid (ALA) synthetase activity results in decreased production of ALA and prophobilinogen (PBG). PORPHYRIA Infection, pregnancy, stress (eg argument) and drugs can precipitate an acute porphyria attack. Common drugs which can precipitate a porphyria attack are: Barbiturates Sulfonamides

chloroquine steroids Drugs which are safe in porphyria are: Aspirin Atropine Glucocorticoids Insulin Narcotic analgesics Phenothiazines Ranitidine Serotonin Reuptake Inhibitors (antidepressants) Streptomycin Acute intermittent porphyria is a autosomal dominant disorder caused by a defect in porphobilinogen deaminase activity. If peripheral neuropathy, such as pain in the back and legs or parathesias occurs it is almost always preceded by abdominal pain. The defect in porphobilinogen deaminase causes a build up of ALA and porphobilinogen (PBG) which causes their increased secretion in the urine. Urine PBG is raised in acute intermittent porphyria, and the urine typically turns a red brown/ red colour on standing. Hereditary coproporphyria (HCP) and Variegate porphyria (VP) have skin manifestations and acute attacks. In variegate porphyria, there is increased production of protoporphyrinogens due to a mutation in protoporphyrinogen oxidase in the haem synthesis pathway. Urinary porphobilinogen is usually normal, unlike acute intermittent porphyria. Variegate porphyria is associated with intermittent abdominal pain, mood disturbances, and a bullous eruption that occurs over sun-exposed areas. Acute attacks do not occur with Porphyria cutanea tarda (PCT). Purpuric rash is the most common presenting feature of cryoglobulinaemia but other cutaneous features which may occur are Raynauds phenomenon, telangiectasiae, urticaria and pigmentation. Hypokalaemic periodic paralysis is a condition associated with hypokalaemia and episodes of weakness which may be profound. The weakness does not usually involve bulbar and respiratory function. This disorder is commonly caused by medication, especially diuretics. Potassium should be given before bicarbonate as bicarbonate can precipitate further hypokalaemia. Other ways of preventing acute exacerbations are avoiding heavy carbohydrate meals, a very low sodium diet and spironolactone. Abetalipoproteinaemia is a disorder in the synthesis of serum lipoproteins containing apolipoprotein B, for example chylomicrons, VLDL and LDL. It is a slowly progressive disorder characterised by: retinitis pigmentosa ataxia areflexia

steatorrhoea motor tics emotional lability, but normal cognitive function Phenylketonuria occurs due to a defective enzyme phenylalanine hydroxylase. Classic PKU is present when plasma phenylalanine levels accumulate and exceed 20 mg/dL (1200 mmol/L). Urinary phenylalanine metabolites are raised. Phenylalanine accumulation causes severe low IQ, microcephaly, epilepsy, depigmentation of the iris and hair. Guthrie bacterial inhibition test is used for infant testing. Fe chloride turns green in urine due to ketones. METABOLIC DISORDERS Severe hyponatraemia can cause seizures, obtundation/decreased conscious level, headaches, upper motor neuron signs (central pontine myelinolysis), bradycardia (not tachycardia), hypotension and mydriasis. Causes of hypomagnesaemia: Loop diuretics Aminoglycosides Cyclosporine amphotericin cisplatin Common causes of rhabdomyolysis are: Alcohol barbiturates heroin overdoses metabolic disorders (DKA, HONK, hyponatraemia, hypokalaemia, hypothyroidism). Normal anion gap metabolic acidosis: The normal anion gap is 8-16. The anion gap in this question is Na+K-(Cl+HCO3) . The causes of a normal anion gap metabolic acidosis are renal tubular acidosis, ileal conduit, carbonic anhydrase inhibitors, ammonium chloride ingestion. Ureterosigmoidostomy The causes of a increased anion gap metabolic acidosis are toxicity with salicylates ethylene glycol toluene lactic acidosis diabetic ketoacidosis

Nephrocalcinosis is related to type I (distal) renal tubular acidosis. It also causes hyperchloraemic metabolic acidosis (it is one of the causes of normal anion gap metabolic acidosis). Type II (proximal) renal tubular acidosis is typically related to a Fanconi syndrome (loss of amino acids, glucose, phosphate and uric acid into the urine). Type 4 RTA is caused by a defect in the distal tubule, but it is different from classic distal RTA and proximal RTA because it results in hyperkalaemia rather than hypokalaemia. RTA type 4 is in effect hyporeninaemic hypoaldosteronism. It occurs when blood levels of aldosterone are low or when the kidneys do not respond to it. Fludrocortisone is usually effective as a form of treatment. Type IV RTA may result from may result from sickle cell disease, urinary tract obstruction, lupus, amyloidosis, or transplantation. Liddle's syndrome is an autosomal dominant condition leading towards increased renal tubular (collecting tubule) resorption of Na and in most cases potassium loss. There are classically low renin and aldosterone levels and normal cortisol levels. The cause is increased activity of luminal membrane Na channels. Treatment is with triamterene or amiloride. Bartter's syndrome is an autosomal recessive renal disorder. Presentation is often in childhood with gastrointestinal upset and polyuria. There is associated hypokalaemic alkalosis, elevated renin and aldosterone levels. Vomiting, constipation, polyuria and polydipsia are common symptoms.

MALARIA Cerebral malaria is only caused by Plasmodium falciparum. Falciparum malaria can also cause hepatitis, gastrointestinal symptoms(diarrhoea), glomerulonephritis/acute tubular necrosis and blackwater fever. Plasmodium ovale is the rarest of the four species and is apparently more restricted in distribution. However, it is common in the West African countries of Ghana, Liberia, and Nigeria. Plasmodium vivax and ovale are the only ones which have liver parasite dormancy. Hypnozoites in the liver spread to the bloodstream and become trophozoites in the rbc and progress through asexual reproduction to merozoites which are released. Plasmodium vivax and ovale only infect reticulocytes whilst falciparum infects erythrocytes of all stages and malariae infects mature erythrocytes. The Duffy blood group is essential for vivax spread as the merozoites of these attach to the Duffy receptor on red blood cells.

Plasmodium malariae causes quartan fever (every 72 hours or fourth day) whereas the other species cause tertian fever (every 48 hours or third day). Quinine can be given orally to treat falciparum malaria. Intravenous quinine is indicated in complicated malaria e.g. cerebral malaria and hyperparasitaemia (>2%). Hypoglycaemia is an important side effect of quinine therapy (causes insulin release) and BMs should be checked 2 hourly. MENINGITIS Meningococcal meningitis: Immunisation is available against strains A, C and W135 of this bacterium, however strain B is the most often implicated in meningococcal meningitis in the UK. Rifampicin, ciprofloxacin and ceftriaxone can be used for prophylaxis. Pneumococcal meningitis is caused by gram positive diplococci (meningogoccus = gram negative diplococci). The young and elderly are most at risk. Nerve deafness is likely, paralysis can occur and mortality rate is high among the elderly. Intravenous penicillin or ceftriaxone should be given. Vancomycin and rifampicin can also be used. Dexamethasone is indicated in early infection to prevent neurological sequelae. Tuberculous meningitis: Symptoms are headache, vomiting, photophobia, and fever. The duration of presenting symptoms may vary from 1 day to 9 months. CSF typically shows elevated protein level, markedly low glucose, and a pleocytosis, initially polymorphs then lymphocytes. Treatment of TBM includes isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (quadruple therapy). Steroids are usually also indicated (except in mild cases) to prevent neurological sequelae.

Viral meningitis: A combination of lymphocytosis, normal or mildly elevated protein and normal glucose suggests viral meningitis. Common causes include enterovirus and mumps. Listeria meningitis is generally associated with multiple cranial nerve deficits, particularly of the VIth and VIIth nerves, as well as hemiparesis, ataxia and respiratory abnormalities often leading to respiratory arrest. High dose (eg 2g qds IV) ampicillin or amoxycillin are the treatment of choice. FUNGAL DISEASES Candida infection commonly causes mucosal disease (eg. Vulvovaginitis and oral thrush). Opthalmitis (causing blindness if not rapidly diagnosed) and line related sepsis can also occur. Disseminated candidiasis can cause fever and painless red papular lesions in the upper and lower limbs, especially in the immunocompromised (e.g. post transplantation). The diagnosis can usually be made on blood cultures but the organisms can be seen in the lesions on biopsy. Common sites of dissemination include the head, eyes, renal parenchyma (fungal balls), liver, and spleen. Coccidiodes manifests similar to histoplasmosis and spreads to the lymph nodes. Intradermal tests are diagnostic. Treatment is with amphotericin. Pityriasis versicolor (also called tinea versicolor) is a skin infection caused by a fungus called Malassezia furfur. The treatment is topical selenium sulphide or miconazole cream. Griseofulvin is not active against Candida albicans or aspergillus. It is active against trichophytons (tinea or ringworm) and other dermatophytes. It is metabolised in liver (hence caution in liver rather than renal failure). DIARRHOEA The differential is wide for a patient with diarrhoea following a holiday. These include: Iinfection gastroenteritis versus sepsis. Fever > 38.5 degrees is unlikely to occur in simple gastroenteritis and alternative diagnoses should be considered e.g. enteric fever, malaria, respiratory infection etc Post-infectious malabsorptive processes e.g. disaccharide intolerance, bacterial overgrowth Post-infectious irritable bowel Chronic GI disease unmasked by infection: e.g. inflammatory bowel disease, coeliac disease, colorectal carcinoma, HIV infection Traveller's diarrhoea is an extremely common occurrence, affecting up to half of travellers to high risk areas such as Africa, Asia and South America. The commonest infective cause world-wide is Escherichia coli. Shigella, salmonella, campylobacter and amoebic dysentery may be bloody. Cholera (profuse rice-water stools several litres/day) and Giardia (explosive) diarrhoea are never bloody.

Giardia lamblia infection can present with abdominal pains and diarrhoea or steatorrhoea. Duodenal aspirate +-biopsy can confirm the diagnosis. Villous atrophy is associated. Bacillus cereus food poisoning is caused by toxin release. There are two types of toxin, the Diarrhoeal (causing diarrhoea) and the Emetic (causing vomiting). Symptoms with the diarrhoeal toxin are nausea, cramplike abdominal pains hours after ingestion usually of rice and watery diarrhoea. The diagnosis is confirmed by a laboratory test on a faecal specimen. Cryptosporidium is water borne and is a protozoan parasite. Swimming in hot tubs and pools, lakes, ponds are risk factors. It can also be spread via uncooked food. Treatment is conservative. Symptoms typically last for 1-2 weeks but longer in immunocompromised e.g. HIV. VIRUS INFECTIONS Cytomegalovirus (CMV), a type of herpesvirus, is very common. Blood tests show that 60 to 90% of adults have had a CMV infection at some time. Usually this infection produces no symptoms but it may cause a glandular fever-like illness in young adults. Serious infections occur in the immunocompromised. Manifestations include pneumonitis, haemorrhagic colitis, hepatitis, retinitis , leucopenia and thrombocytopenia. Diagnosis is made by detection of CMV antigen or with polymerase chain reaction (PCR) in blood. Tissue biopsy classically shows owls eye inclusion bodies. Ganciclovir, valganciclovir, cidofovir or foscarnet may be given. For people with CMV retinitis, a small device containing sustained-release ganciclovir can be implanted in the eye. Polyoma virus BK is associated with interstitial nephritis in patients with renal transplantation and may cause fever and haematuria, but more commonly presents with impairment of renal function. Treatment of the infection at present is by reduction of immunosuppression. Dengue fever is a flavivirus transmitted by Aedes mosquitoes. It is present in South East Asia, Africa (rare), the Middle East and the Indian sub-continent. The disease has an incubation period of less than 7 days. Headaches, retro-orbital pain, musculoskeletal pains and a maculopapular rash occur. Treatment is conservative with antipyretics and bedrest. Serious disease occurs with reinfection with a different serotype (there are 4) resulting in dengue haemorrhagic fever and dengue shock syndrome. Human T-cell Lymphotropic Virus (HTLV-1) is a retrovirus common in the Carribean. It is also present in Africa and in IVDUs in the USA. It is transmitted via blood, semen and breast milk. It infects T-cells and may result in PCP pneumonia due to immunosuppression although is not cytolytic. It may cause adult T cell leukemia, tropical spastic paraparesis (a demyelinating disease that causes spasticity and weakness usually in middle-aged women in the Carribean), arthritis and polymyositis Measles is increasing in incidence in young adults in the UK due to lack of uptake of MMR. It causes serious disease in African children (worse in vitamin A deficiency), although immunisation has greatly reduced the incidence. Presentation is with fever,

dry cough, conjunctivitis, a descending rash (head travelling down trunk) and lymphadenopathy. White/blue-grey spots on the buccal mucosa are known as Koplik spots and are pathognomonic but only occur in early infection. In young children, latent infection can involve the central nervous system - known as subacute sclerosing panencephalitis. Treatment is with supportive care. Mumps is an RNA virus (like rubella). Its incubation period (time between infection and first symptom) is 7 days. It may cause parotitis, orchitis (affecting fertility in around 5% of bilateral cases), lymphocytic meningitis and occasionally pancreatitis. Bilateral parotitis occurs in 75% of patients. Rubella is a togavirus and an RNA virus. Its incubation period is 18-21 days. Common features of rubella are rash on the forehead, suboccipital lymphadenopathy, polyarthritis and polyarthralgia and Guillain-Barre syndrome. Termination is offered if infection occurs in the first 16 weeks (4 months) due to the high probability of foetal abnormality (>90%). Features seen in congenital rubella are : Microphthalmia , Microcephaly, Cataracts, Patent ductus arteriosus, Peripheral pulmonary artery stenosis, Hepatosplenomegaly, Thrombocytopaenia, Maculopapular rash and Deafness Infectious mononucleosis is caused by the Epstein Barr virus. Fever, sore throat and lymphadenopathy are common, splenic rupture (requiring surgery), bacterial infections and hepatitis may occur. There are raised titres of heterophile antibodies (which recognise a variety of antigens) in 75% of infectious mononucleosis cases. This forms the basis of the Paul Bunnell and Monospot tests which detect foreign red blood cell agglutination with patient IgM antibodies. Herpes simplex viruses (HSV-1 and HSV-2) cause cold sores (usually HSV-1), and painful genital ulcers (usually HSV-2). HSV encephalitis manifests with a triad of fever, seizures and obtundation. The temporal lobe is most commonly involved, as in this case. It may result in long-term memory problems. Herpes simplex virus infection of the skin causes eczema herpeticum. Vesicles can form and coalesce after 7 days from infection. Pyrexia is common during this time. Neurological spread, sepsis and secondary bacterial infection can occur, especially in children. Herpes simplex encephalitis:. There is more inflammation around the temporal lobe, and the EEG changes of discharges at 2Hz occur. Aciclovir should be commenced upon clinical suspicion as PCR result may be a few days.

Keratitis, iritis, iridocyclidis, conjunctivitis, dendriform ulcers on the cornea and secondary glaucoma can occur in Herpes Zoster Opthalmicus which is caused by varicella zoster virus. Herpes virus is a double stranded DNA virus. Herpes encephalitis can be confirmed with PCR .

The influenza virus belongs to the orthomyxovirus group and comprises of three types: Influenza A is the cause of world wide epidemics and pandemics (including avian influenza). Haemagglutinin, a surface glycopeptide aids attachment of the virus to host cells. Viral neuraminidase helps in release of replicated viruses through the cell membrane. Influenza B causes smaller and milder outbreaks. Type C rarely produces disease in humans.

Japanese encephalitis is caused by a RNA virus which endemic in India, East Asia, Malaysia and the Phillipines. Previous infection by a pathogen which a member of the flavivirus family may help to protect against serious disease. Parvovirus infection or fifth's disease causes the 'slapped cheek syndrome'. There is a cheek rash with swollen wrists, hands and knees. Diagnosis can be confirmed with an IgM antibody to parvovirus B19. It may also cause severe anaemia in patients with haemoglobinopathies and in the foetus causing hydrops foetalis. Rabies virus belongs to the genus Lyssavirus within the family Rhabdoviridae. Dogs remain the principal host (other wild animals can transmit) and transmitter of rabies to humans. If bitten by a dog in an endemic area, anti rabies immunoglobulin should be administered, followed by a course of rabies vaccine over 2 weeks. West Nile virus is a mosquito-borne flavivirus. It is an emerging infection affecting to Africa, Asia, Europe, and Australia. It presents as fever, myalgia, nausea and vomiting. It may cause meningoencephalitis and can present with a Guillain Barre like syndrome (depressed tendon reflexes and weakness). IgM antibody against West Nile Virus is diagnostic. Treatment is supportive.

HUMAN IMMUNODEFICIENCY VIRUS There are 2 forms of HIV, 1 and 2. The genome contains RNA and it is a retrovirus. The HIV genome contains the genes: tat and rev along with nef, env, gag and pol. Gp 120 is the major protein on the surface of HIV that interacts with host cells. It binds to CD4 receptors. HIV binds to cell surface CD4 but enters cells through chemokine coreceptors including CXCR4 and CCR5. Viral protease (not host protease) cleaves products of gag and pol. Gag (group specific antigen) codes for antigens including Viral Capsid Antigen p24. Pol (polymerase) codes for viral protease, reverse transcriptase and DNA POLymerase. Common organisms such as entamoeba, salmonella, giarda, campylobacter, cryptosporidium, cyclospora, mycobacterium and also viral causes can cause diarrhoea in HIV positive patients. Opportunistic infections considered AIDS defining diagnoses are Pneumocystis, Mycobacterium avium intracellulare, CMV, cryptosporidium, JC virus (PMLE). Pneumocystis jeroveci (carinii) may be identified on microscopy after (a) methenamine silver staining which shows a cystic phase of the organism (b) Giemsa staining which demonstrates sporozoites and trophozoites with small, punctate nuclei. Pneumocystis pneumonia is the commonest AIDS defining illness in Europe. Interstitial shadowing which looks fluffy is common on the CXR which may be normal in appearance. Mortality rate is around 20%, (not 50%) if untreated. Type I respiratory failure (hypoxia and low CO ) is most common and can be treated with CPAP.
2

Prophylaxis with co-trimoxazole (or dapsone or pentamidine if allergic) is indicated when CD4+ counts are less than 200.

Progressive multifocal leukoencephalopathy (PML) is caused by chronic infection with JC virus, and causes white matter lesions in the brain. A CD4+ of <100 predisposes to the condition although it may occur at higher levels. JC virus invades oligodendrocytes, which manufacture myelin, causing demyelination. Hemiparesis, aphasia, cortical blindness, ataxia and altered mental state may occur with an insidious onset of dementia. Anti-retroviral therapy including a protease inhibitor is the main treatment for PML and cidofovir may also be used. Antiretrovrial therapy is initiated in asymptomatic patients when the CD4 count approaches 200. It is also initiated in patients with symptomatic disease and higher CD4 counts and considered in symptomatic seroconversion illness. Protease inhibitors, such as atazanavir, saquinavir, ritonavir and indinavir (NB the exception is abacavir which is an NRTI) are associated with lipodystrophy, insulin resistance, and disturbed fat and glucose metabolism Indinavir crystallises in the renal tract leading to renal impairment and stones Nucleoside reverse transcriptase inhibitors (NRTIs) such as AZT (zidovudine) are associated with lactic acidosis, peripheral neuropathy, pancreatitis as a result of mitochondrial toxicity. Lamivudine is the least likely agent to cause symptoms and is generall well tolerated. AZT (Zidovudine) may cause bone marrow suppression leading to anaemia. It induces a grey discolouration of the nails in persons with pigmented skins. Peripheral neuropathy also occurs. It may also cause proximal myopathy. DDI (Didanosine) is a nucleoside analogue. It causes pancreatitis. Abacavir may cause a lifethreatening hypersensitivity reaction including rash, diarrhoea and fever. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcriptase non-competitively. Nevirapine may cause Stevens Johnsons syndrome/ rash and deranged LFTs. Efavirenz may cause severe depression and deranged LFTs.

VACCINES Live vaccines (attenuated) easiest to memorise these (all others=inactivated) BCG Mumps Measles Rubella Yellow fever Smallpox Oral polio vaccine (this is a live vaccine) should not be given immunosuppressed children, their siblings or household contacts. Besides the "live" oral polio vaccine (Sabin), there is also an inactivated (killed) polio vaccine (Salk) given by injection which protects against polio after several shots. Other vaccines Meningococcal A/C +- W135 is a polysaccharide vaccine. Cholera and hepatitis A are both inactivated viral vaccines. Tetanus is a toxoid. The UK immunisation schedule is : Haemophilus influenzae type b (Hib) 2, 3 and 4 months Diptheria/Pertussis/Tetanus (DPT) Meningococcus Group C Oral Polio vaccine (OPV) Measles/Mumps/Rubella (MMR) 13 months Further OPV, D/T at 5 years BCG 10 - 14 years Hepatitis B is also given to those at risk (those with infected family members) Mengococcal Vaccines recommended in those at high risk to exposures (contact or health workers), immunodeficiency and post splenectomy.

SEXUALLY TRANSMITTED DISEASES Primary syphillis causes a chancre and inguinal lymphadenopathy in the first weeks. Secondary syphillis (following few months) manifests as generalised lymphadenopathy, maculopapular rash (affecting hands and feet), fever, infectious papules around the perinanal regions (condylomata lata) and snail track ulcers in the mucous membranes of the mouth. In tertiary syphillis (usually >2 years), gumma formation (granulomas) may occur cutaneously and in the mucosal region, liver, stomach and lungs. Cardiovascular syphilis may lead to aortic regurgitation as a result of a dilated aortic root and quaternary syphilis is manifested by neurological sequelae including general paralysis of the insane, focal neurology (syphilis is the great imitator and dementia. Successful therapy may be monitored by a fall in VDRL or rapid plasma reagin (RPR) titre (if these were initially positive 75% have positive VDRL in primary, 99% secondary and variable results in tertiary/quaternary syphilis). In toxocariasis, granuloma forms around the larvae which are spread by dogs and cats. Fever, hepatomegaly and respiratory symptoms constitute visceral larval migrans. Treat with thiabendazole. Amoebiasis tends to abscess formation. 'Elephantiasis' affects the lymphatic system, causing swollen legs. The organisms are filariae called Wuchereria bancrofti or Brugia malayi. In acute infection, organisms

can be detected on a blood film, and filarial serology can be sent. Treatment is with diethylcarbamazepine (DEC) or ivermectin. Gonorrhoeae infection. Can cause penile discharge and knee effusions with rash. The discharge and knee aspirate may grow gram negative diplococci. Ttreatment is with ceftriaxone IM single dose. Concurrent treatment for chlamydia should be given for 3-6 weeks, to include oral tetracycline 500 mg 4 times a day or oral doxycycline 100 mg twice a day. A patient presenting with urethral discharge may have gonococcal or non-gonococcal urethritis (NGU). If there are no gram negative diplococci seen on microscopy, it is likely to be NGU. The organisms causing NGU are as follows: Chlamydia trachomatis 40% Ureaplasma urealyticum 20-40% Trichomonas vaginalis (rare) < 2% Candidasis (rare) < 2% Herpes simplex (rare) < 2% The differential diagnosis of genital ulceration includes not only the lesions of chancroid, lymphogranuloma venereum and granuloma inguinale, but also those of herpes simplex virus infection and primary syphilis (chancre) Multiple painful genital ulcers with localised lymphadenopathy may suggest chancroid, which is caused by Haemophilus ducreyi. Treponema pallidum infection causes (syphilis), which presents as a solitary painless chancre. Chlamydia trachomatis causes lymphogranuloma venereum, which presents as a painless ulcerating papule and regional lymphadenopathy. Klebsiella granulomatis causes Donovanosis, which presents as a heaped up ulcerating lesion with prolific red granulation tissue on the external genitalia. Trichomaonas vaginalis is a protozoan. It is a very common sexually transmitted infection in the developing world. Men are only mildly symptomatic with urethritis and it is not a cause of genital ulceration. HELMINTHS / WORMS Note: Tissue invasive helminth (worm) infections may cause eosinophilia. Protozoan parasites e.g. malaria, amoebae do not. Ascaria lumbricoides is a roundworm which infects the ileum and may cause GI symptoms. It also causes pneumonitis and bronchospasm when the larvae migrate via the bloodstream to the alveoli (Lofflers syndrome). Once mature they crawl back up the bronchi into the gut. Ankylostoma duodenale/Necator americanis are hookworms. They hook to the intestine and secretes anticoagulants to ingest blood. They enter the lungs via lymphatics after penetration through the skin, and also ascend the bronchi to enter the gut when mature. Cutaneous larva migrans, caused by various Ankylostoma (hookworm) species is characterised by a slowly lengthening, serpiginous, intensely itchy rash. Strongyloides is a helminth which may be aquired both via the skin as with hookworms or by ingestion.

Taenia solium is the pork tapeworm which is spread by ingesting undercooked pork. The eggs of the worm spread through the gut, liver and encyst in the CNS, muscles and eye to cause cysticercosis. Hence it may result in epilepsy and cranial nerve palsy, muscle hypertrophy and blindness. It does not affect the lung. Taenia sagitana is the beef tapeworm and does not cause cysticercosis. Schistosoma larvae (cercariae) released from snails swim in water and penetrate human skin, enter the bloodstream to spread to both the lungs and liver. Hepatic and pulmonary fibrosis occurs and also the specific manifestations of the different species (mansoni, japonicum and haematobium). Echinococcus is the cause of hydatid cysts. It is ingested into the gut after handling of dogs (dog tapeworm) and enters both portal and pulmonary circulation. Hydatid cysts and alveolar cysts form. Treatment of choice is surgical excision plus albedazole and praziquantel with a high risk of cystic rupture with metastatic spread of organisms and anaphylaxis. MISCELLANEOUS Amoebiasis is caused by Entamoeba histolytica is spread by faeco oral route. It can present months or even a year after infection. RUQ and referred pain to the shoulders (not always present) and fever are common presentations. RUQ discomfort may be worsened by alcohol. Amoebic dysentery (bloody diarrhoea) is treated with oral metronidazole or tinidazole. Trophozoites invade the intestine to penetrate the liver via the portal circulation causing liver abscess (often without diarrhoea). Cysts cause re-infection and spread to other people (and do not reach the liver). Cysts are not treated with metronidazole and diloxanide may be used to eradicate these. Liver abscesses can be solitary or multiple and usually affect the right lobe. Liver abscesses require treatment with metronidazole. Surgical drainage is indicated if they are near to the capsule of the liver or very large. Actinomyces is a gram positive bacillus which behaves like a fungus, causing actinomycetoma deep tissue infection which is granulomatous. Nodules develop under the skin and erupt to discharge grains. Nocardia is another gram positive bacillus which may appear acid-fast. It causes infection in immunosuppressed individuals causing fungal-like activity of mycetoma formation in the lungs and other organs. It is treated with co-trimoxazole. Arthropod borne infections. Arthropods comprise of ticks, spiders and insects. Babesiosis is transmitted by tick bites. Trypanosomiasis is spread by the tsetse fly. Yellow fever is spread by the Aedes mosquito. Onchocerciasis (river blindness) is spread by blackflies. In onchocerciasis, there are skin nodules occurring due to an inflammatory reaction and also severe keratitis / conjunctivitis. Loa loa is spread by the Chrysops fly and causes Calabar swellings and conjunctival worms which may be seen by the patient crawling across the eye. Anthrax is caused by a gram positive, aerobic, bacillus called Bacillus anthracis. In humans, cutaneous anthrax commonly causes a painless, black, indurated eschar

typically with massive surrounding oedema. Mortality from cutaneous disease is 20% if untreated whereas inhalational anthrax may have a mortality of 90% if untreated. Inhalational anthrax has a poor yield from sputum culture and characteristically causes a haemorrhagic mediastinitis. The prodrome includes high fever and rapid deterioration follows. Treatment is with IV penicillin. Prophylaxis is with ciprofloxacin. Botulism typically produces a descending paralysis which starts with diplopia or blurred vision due to cranial nerve involvement, difficulty with accommodation and progresses to weakness of the neck, arms and respiratory muscles. Botulism is caused by the neurotoxins of Clostridium botulinum and in rare cases, Clostridium butyricum and Clostridium baratii. These gram-positive spore-forming anaerobes can be found in soil samples and marine sediments throughout the world. Therapy consists of approximately 10,000 IU of antibodies against toxin types A, B, and E to neutralize serum toxin concentrations, and also supportive care (e.g. ventilation). It may be acquired by ingestion of toxin or more commonly in the UK wound infection as a result of intravenous drug use. Brucellosis is caused by G ve coccobacilli which spread through untreated milk and raw beef and may affect all systems. B. abortus (cattle), B. suis (swine), B. melitensis (goats), B. canis (dogs) are the different organisms. Detection of brucella requires extended blood culture of up to 6 weeks. Leucopenia is common. Detection of Brucella agglutinins also helps confirm the diagnosis. Spondylitis or osteomyelitis, endocarditis, pneumonia, liver granuloma and jaundice and pyelonephritis. Treat with doxycycline and rifampicin or aminoglycoside for synergistic effect. Diphtheria: Corynebacterium diphtheriae causes diphtheria. It is a gram positive rod. It may present with sore throat, fever and lymphadenopathy, heart failure or neurological damage. A greyish pseudomembrane can also form on affected areas such as the skin, pharynx and conjunctivae. The illness is still present in Eastern Europe and Russia. Treatment is with diphtheria antitoxin, penicillin or erythromycin. Klebsiella pneumonia is a disease commonly affecting middle aged to older men with alcoholism. Klebsiella pneumonia characteristically affects one of upper lobes of the lung. There is an increased tendency toward abscess formation. Mycoplasma pneumoniae infections have a more insidious onset, affect younger patients e.g. in barracks and is associated with systemic symptoms esp headache. Legionnaire's disease is usually due to infection with Legionella pneumophila type 1. Male sex, smoking, high alcohol intake, pre-existing immunocompromise and COPD are risk factors. Rifampicin alone increases resistance and is not as effective as 3 weeks of erythromycin Leishmaniasis (Kala Azar) is spread by bites from sandflies. Cutaneous lesions can occur at the site of the bite. Visceral leishmaniasis can occur, causing massive hepatosplenomegaly. Smears from bone marrow/spleen show Donovan bodies (amastigotes of Leishmania donovani). Cutaneous leishmaniasis may be divided into that of the Old World (Africa, Mediterranean, Afghanistan) and cutaneous leishmaniasis of the New World (Central and South America). Cutaneous leishmaniasis can be caused by several Leishmania

species, including L. braziliensis, L. mexicana and L. panamensis. The incubation period is variable, ranging from 2 weeks to several months. Cutaneous leishmaniasis of the Old World heals in 4-18 months leaving a scar. No serious sequelae occur. It may be left alone but is usually treated with intra-lesional sodium stibogluconate therapy. New World cutaneous leishmaniasis should be treated due to the risk of mucocutaneous disease and sodium stibogluconate is given intravenously. Visceral leishmaniasis is most commonly caused by Leishmania donovani. Fever, malaise, anaemia, weakness and weight loss are common. Hepatosplenomegaly develops gradually and the skin may become grey. Listeria monocytogenes is an aerobic and facultatively anaerobic gram-positive bacillus. The risk of listeriosis is markedly increased in immuno-compromised patients, particularly among those undergoing renal transplantation, receiving high doses of corticosteroids, or suffering with AIDS or cancer. Ampicillin or penicillin has generally been recommended as the treatment of choice. It causes septicaemia in pregnant women and meningitis in older men. Neurocysticercosis is caused by Taenia solium (pork tapeworm). There may be seizures due to localised inflammation that accompanies their degeneration in the cerebral cortex when calcified cysts occur. This disease is found in South America and Asia. Neurocysticercosis typically is benign, and most lesions resolve spontaneously within 2-3 months. CT or MRI of the head may show granulomatous cysts. An enzyme-linked immunotransfer blot (EITB) assay of a patient's serum may confirm the diagnosis. Approximately 65-80% of children diagnosed with neurocysticercosis present with seizures, most often focal in nature. Increased intracranial pressure (due to hydrocephalus, which can occur in 15-25% of cases) causes other common clinical symptoms, including headache, nausea, and vomiting. Albendazole is the recommended treatment. Lyme disease is caused by Ixodes tick bites spreading Borrelia burgdorgferi. A targetlike rash called erythema chronicum migrans is associated. Arthralgia, heart block and meningitis (sometimes with bilateral VII nerve palsy) may occur. Treatment is with doxycycline orally or IV ceftriaxone for complicated cases. Pasteurella multocida is found in the snouts of both dogs and cats. Soft tissue infection results following bites and may progress to tenosynovitis, osteomyelitis or lymphangitis depending on the site of the bite. Drug therapy is with co-amoxiclav. Pertussis (Whooping cough) is caused by the gram negative bacterium Bordetella pertussis. Infection is characterised by paroxysms of coughing. Lymphocytosis is commonly seen. Hemiplegia/hemiparesis is a recognised consequence of severe whooping cough. Pseudomembranous colitis (Clostridium difficile) is rare with aminoglycosides, probably because they have little activity against anaerobic gut flora. Long-term therapy and renal impairment increase the risk of ototoxicity. Neutropenia and aplastic anaemia may be seen. Nephrotoxicity is usually of an ATN/proteinuria type and is usually reversible on withdrawal of the drug.

Psittacosis is caused by Chlamydia psittaci. It is spread by all sorts of birds, not just pigeons or parrots. Children are less predisposed than adults to the disease. Treatment is with tetracycline or doxycycline. Q fever is due to Coxiella burnetii and is acquired via animal contact. It is not notifiable, but can occur in outbreaks in farming communities and in abbatoirs. Treatment is with prolonged courses of tetracyclines. Rickettsioses range in severity from diseases that are usually relatively mild (rickettsial pox, cat scratch disease, and African tick-bite fever) to those that can be life-threatening (epidemic typhus, Rocky Mountain spotted fever, and Oroya fever). They are often characterised by rash, an eschar and maculopapular rash. Schistosoma haematobium infection is associated with eosinophilia. The sexual replication stage may occur in humans or other animal hosts. The asexual stage occurs in snails. Although most of the eggs are laid by the parasite in the bladder (cystitis, granulomas, haematuria), some are deposited in the rectum and a rectal biopsy may yield the diagnosis. The larvae can travel to the lungs and cause pulmonary hypertension. Hepatomegaly is more typical of S mansoni and S japonicum rather than haematobium. Scabies is spread by Sarcoptes scabei. It is spread by contact only. Effective agents are benzyl benzoate, ivermectin and permethrin (Lyclear solution). Staphylococci and Streptococci: Benzylpenicillin will cover Streptococci and flucloxacillin will cover Staph aureus. Staphylococcus aureus has the ability to colonise the nasopharynx and/or skin or cause a wide variety of clinical diseases. Its major disease manifestations include: cellulitis osteomyelitis and septic arthritis other suppurative infections e.g. intra-abdominal abscesses, perinephric abscesses, empyema or paraspinal abscesses septicaemia and endocarditis respiratory disease including pneumonia and empyemas toxin related disease toxic shock syndrome, food poisoning, scalded skin syndrome The presentation of pyrexia, shock, diarrnoea and vomiting, myalgia, desquamating rash and mucous membrane involvement is consistent with toxic shock syndrome. It can also present with abnormal liver and renal function, as well as thrombocytopenia. Toxic shock syndrome can be caused by both staphylococcus (tampon related or skin infection) and streptococcus (skin infection). Streptococcus bovis usually enters the bloodstream via the gastrointestinal tract. Nearly all patients with S bovis endocarditis are older than 50 years, and there is also an association with malignancy of the GI tract. Treatment is with penicillin or vancomycin and gentamicin. Toxoplasmosis causes microcephaly rather than macrocephaly. Choroidoretinis, cerebral mass, lymphadenopathy and myocarditis also occur. Lymphadenopathy is

earliest typical feature of this parasite which is spread by cats. It typically causes neurological damage and ocular damage. Cysts are found in cat faeces in soil and multiply intracelullarly as tachyzoites after spread through the gut, bloodstream and lymphatics. Treatment is with Pyrimethamine and Sulfadiazine. Tuberculosis : The BTS guidelines recommend that a six month regimen comprising rifampicin, isoniazid, pyrazinamide, and ethambutol for the initial two months followed by rifampicin and isoniazid for a further four months is a standard treatment for adult respiratory tuberculosis. Pyridoxine is also given with the therapy. Isoniazid may cause pyridoxine and nicotinic acid deficiency due to its effect on the liver. Tetanus sometimes known as lockjaw is a disease manifested by uncontrolled spasms, due to the introduction of Clostridium tetani toxin into tissues. Skin punctures, contaminated wounds with soil, dust, burns have played a role in the development of the disease. The spores produce a neurotoxin (tetanospasmin) which causes severe spasm all over the body which leads to painful muscle contraction and laryngeal spasm which interfere with breathing and muscle tears. The incubation period is typically between 1-2 weeks. Vaccination with tetanus toxoid has been proved to be effective since its introduction in 1920's. Booster immunization to whom has been injured it is advisable for those who the last immunization received was about 10 years or more. The conventional treatment of severe tetanus which is supportive along with penicillin, is still the most effective treatment. Typhoid fever: Positive cultures may be obtained from blood, bone marrow, urine, faeces, rose spots and bile. Whipples disease typically presents as a gastrointestinal illness caused by the organism Tropheryma whippei. The illness is characterized by diarrhea, abdominal cramps, and sometimes frank malabsorption. If gastrointestinal disease is prominent, duodenal biopsy is performed, it often yields evidence of Trophyrema whippei by light microscopy, electron microscopy, or PCR, allowing the diagnosis to be substantiated. Histopathologically, one sees macrophages containing periodic acid-Schiff (PAS)positive material. The characteristic rod-shaped intracellular organism is seen by electron microscopy. Current recommendations are for a two-week course of intravenous ceftriaxone, to be followed by one to two years of double-strength oral trimethoprim-sulfamethoxazole.

HLA ASSOCIATIONS The HLA system plays a role in antigen presentation and self recognition. HLA A, B and C are all encoded by MHC class I, not class II. Class II MHC molecules encode HLA D, which serve as antigen recognition molecules for T helper cells. HLA B8, DR3 and DW3 are associated with autoimmune hepatitis and Sjogrens syndrome. HLA-B5, HLA -B51 and HLA-DR5 are associated with Behcets syndrome. Decreased HLA DR2 is associated with narcolepsy, HLA DR3 is associated with many autoimmune conditions, autoimmune adrenalitis (Addisons) Increased HLA DR4 is associated with rheumatoid arthritis, autoimmune adrenalitis (Addisons) The most commonly found HLA in coeliac disease (almost 90%) is HLA DQ2 and HLA DQ8. HLA B27 is commonly associated with ankylosing spondylitis, reactive & psoriatic arthritis, Reiter's syndrome and Whipple's disease. OSTEOMALACIA AND OSTEOPOROSIS Osteomalacia is characterized by a low serum calcium and phosphate with elevated serum alkaline phosphatase. Osteomalacia may be caused by deficiency of vitamin D or phosphate deficiency. Malabsorption syndromes, renal failure and liver disease can result in vitamin D deficiency. Looser s zone are linear areas of low density surrounded by sclerotic borders, which are a feature of osteomalacia. In adults, treatment is with a daily dose of calciferol (20-25 micrograms). Causes of osteoporosis are : postmenopausal women Cigarette smoking eating disorders such as anorexia nervosa or bulimia hypocalcaemia heavy alcohol consumption corticosteroids /Cushing's syndrome anticonvulsants Medications for Osteoporosis: Calcium and vitamin D oestrogen replacement selective oestrogen receptor modulator (SERM) bisphosphonates

The T score is usually used to make treatment decisions using standard deviation (SD). The SD measures the difference between the BMD and that of a healthy young adult (the reference value). Every -1 SD ("minus 1 standard deviation") equals a 10 to 12% decrease in bone density. T score results are classified as follows: A T score between 0 and -1 standard deviation (SD) is considered to be normal. A T score between -1 and -2.5 SD is classified as osteopenia (low bone mass). A T score of 2.5 SD or less is classified as osteoporosis (very low bone mass). Osteopetrosis is caused by increased bone density due to defective osteoclastic activity. GOUT AND PSEUDOGOUT Pseudogout positively birefringent crystals Gout negatively birefringent crystals Pseudogout causes are: Haemochromatosis wilson's disease alkaptonuria (ochronosis) hypothyroidism hyperparathyroidism hypomagnesaemia hypophosphataemia In gout, serum uric acid is elevated in 50% of patients, and often not so in an acute flare up. Inflammatory markers are often raised and the patient may be pyrexial in acute gout. Synovial fluid analysis should be undertaken without delay. Gout is associated with : Hypertriglyceridaemia diabetes obesity Excessive alcohol use chronic renal failure hypothyroidism hyperparathyroidism myeloproliferative lymphoproliferative disease psoriasis Drugs reducing uric acid levels in Gout: xanthine oxidase inhibitor (allopurinol) or a uricosuric drug (sulfinpyrazone) Uric acid results from the breakdown of purines. Purines are found in many foods, for example: Beer and other alcoholic beverages. Anchovies, sardines in oil, fish roes,

herring, Yeast, Organ meat (liver, kidneys, sweetbreads), Legumes (dried beans, peas). RHEUMATOID ARTHRITIS Rheumatoid arthritis causes subcutaneous nodules over the elbows, swelling of the wrists, ulnar deviation at the metacarpophalangeal joints, Butoinneires deformity, dinner fork deformity and swelling of the proximal interphalangeal joints. Periarticular erosions on the X ray are suggestive of rheumatoid arthritis. Disease Modifying Anti Rheumatic Drugs (DMARDs) used in Rheumatoid arthritis. D-penicillamine, gold, antimalarials, choloroquine, sulfasalazine, leflunomide, methotrexate. NSAIDs are important in symptom relief, but do not prevent disease progression. Anti-TNF drugs are this group infliximab, etanercept and adalimumab. The criteria for treatment are that the patient has been treated with at least two DMARDs (diseasemodifying) drugs but continue to have active rheumatoid arthritis. Felty's syndrome consists of a triad of neutropenia, hypersplenism and rheumatoid arthritis, The pulmonary complications of rheumatoid arthritis are : pulmonary fibrosis (interstitial lung disease) bronchiolitis obliterans with organizing pneumonia bronchiectasis interstitial pneumonitis secondary to drugs exudative pleural effusions Caplans syndrome (pneumoconiosis, pulmonary nodules) OTHER ARTHRITIS Psoriatic arthritis presents as several forms: symmetrical polyarthritis arthritis involving DIP joints asymmetrical oligoarthritis including dactylitis Ankylosing Spondylitis type HLA B27 positive sacroilitis arthritis mutilans Osteoarthritis Bouchards nodes are proximal interphlangeal nodes. Heberden's nodes are distal interphalangeal nodes. X ray features of osteoarthritis are: joint space narrowing

osteophytes subchondral sclerosis subchondral cysts Juvenile chronic arthritis is rheumatoid factor negative. Commonest type is Stills disease. Peaks of disease are about 5 years and 15 years of age. A high swinging fever is typical. An erythematous rash can occur, but it is non purpuric. Haematuria is not typical. Certain forms can involve only one or two large joints only. Different classifications are systemic, pauciarticular and polyarticular. Diagnostic criteria include high fever, hepatomegaly, splenomegaly, lymphadenopathy, serositis (pleuritis, pericarditis), leucocytosis. Bone destruction and micrognathia occurs. Gonoccocal arthritis classically presents with a hot joint on a background of a migrating polyarthropathy. It affects women more frequently than men (4:1) and its highest incidence is among sexually active adolescent girls. There is also increased risk during menstruation and pregnancy. Two forms of arthritis exist -- one with skin rashes and multiple joint involvement, and a second, less common, form in which disseminated gonococcemia leads to infection of a single joint (monoarticular) and joint fluid cultures are positive. VASCULITIS Positive ANCA : PR3 (Wegener's) and MPO (microscopic polyangitis) Wegener's affects small vessels particularly in the kidneys. Flare ups can vary with season. Takayasu's and giant cell arteritis both affect large vessels. Churg strauss patients present with asthma and eosinophilia. Polyarteritis nodosa. PAN causes transmural necrotizing inflammation of small-sized or medium-sized muscular arteries. PAN is a rare condition. Although the causes are unknown in most cases, there is an association with: Hep B virus, Hep C virus, HIV, Cytomegalovirus, Parvovirus B19 and Human T-lymphotrophic virus. Approximately 20% of patients with classic PAN are positive for P-ANCA. Steroids (prednisolone) and immunosuppressive (cyclophosphamide) medications form the backbone of therapy. Plasma exchange is useful as a second-line treatment in PAN refractory to conventional therapy. The American College of Rheumatology (ACR) has proposed 6 criteria for diagnosis of Churg Strauss syndrome. The presence of 4 or more criteria yields a sensitivity of 85% and a specificity of 99.7%. These criteria are (1) asthma (wheezing, expiratory rhonchi) (2) eosinophilia of more than 10% in peripheral blood (3) paranasal sinusitis (4) pulmonary infiltrates (may be transient)

(5) histological proof of vasculitis with extravascular eosinophils (6) mononeuritis multiplex or polyneuropathy TENDON & FASCIA De Quervain's tenosynovitis is inflammation of the abductor pollicis longus and extensor pollicis brevis. Finkelstein's test is positive. This is performed with the thumb flexed across the palm of the hand, asking the patient to move the wrist into flexion and ulnar deviation. This stresses the tendons of abductor pollicis longus and extensor pollicis brevis and reproduces the pain of de Quervain's tenosynovitis. Supraspinatous tendonitis: pain during abduction with limitation of movement is suggestive. Palpation or compression around the greater tubercle of the humerus causes tenderness. Eosinophilic fasciitis is a disorder characterized by peripheral eosinophilia and fasciitis. Swelling and progressive induration of the skin associated with aching of the extremities and occasional morning stiffness develop over a period of weeks. The distribution most often is in the upper extremity, proximal and distal to the elbow, and in the lower extremity, proximal and distal to the knee. Onset may be acute following some sort of strenuous exercise, or it may be subacute. The diagnosis is confirmed by deep biopsy from skin to muscle. DRUGS Methotrexate may lead to macrocytosis as a result of B12 or folate deficiency. It may also be associated with bone marrow suppression, causing leucopenia or thombocytopaenia. Methotrexate may also cause mouth ulcers, stomatitis, cough and dyspnoea and rarely, a severe pneumonitis. Allopurinol blocks uric acid production and is the drug most often used in long-term treatment for older patients and overproducers of uric acid. Allopurinol is taken orally once a day in doses of 100 mg to 600 mg, depending on the patient's response to treatment. Between 3% to 5% of patients experience leukopenia, thrombocytopenia, diarrhea, headache, and fever. Hydralazine, procainamide, isoniazid, chlorpromazine, D penicillamine & methyldopa can result in drug induced lupus. Hydroxychloroquine and chloroquine are used to treat SLE. MISCELLANEOUS Causes of sacroilitis: ankylosing spondylitis Crohn's disease Whipple's disease ulcerative colitis septic arthritis TB Wegener's granulomatosis Causes of mononeuritis multiplex are: Rheumatoid arthritis

amyloidosis diabetes leprosy sarcoidosis Churg Strauss Wegeners granulomatosis Polyarteritis nodosa Causes of avascular necrosis of the bone: SLE Nephritis vasculitis long term steroids sickle cell disease Causes of Charcots joints: diabetic neuropathy, syphillis syringomyelia leprosy Causes of Iritis: Behcet's disease Reiter's syndrome ankylosing spondylitis sardoidosis Ankylosing Spondylitis The male:female ratio is 5:1 in ankylosing spondylitis. HLA B27 is more prevalent among caucasians. The typical patient is the young male who complains of morning back (spinal involvement) stiffness. Antiphospholipid syndrome (APS) is a disorder characterized by recurrent venous or arterial thrombosis and/or fetal losses associated with typical laboratory abnormalities. It is also known as Hughes syndrome. These include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine). Vascular thrombosis - DVT, MI, CVA or miscarriages may occur. Other features are nonthrombotic neurologic symptoms, such as migraine headaches, chorea, seizures, transverse myelitis, Guillain-Barr syndrome, thrombocytopenia or hemolytic anemia, Livedo reticularis, Avascular necrosis of bone and Pulmonary hypertension. Aspirin or warfarin is recommended for patients with thrombotic syndromes. A positive ANA (speckled pattern), raised CK and positive anti RNP antibody suggests mixed connective tissue disease.

AntiRo antibody is also associated with congenital complete heart block. When congenital complete heart block occurs, SS-A antibodies are almost always present in maternal and fetal serum (maternal anti-Ro(SS-A) antibody crosses the placenta). Behcet's syndrome is classically characterized as a triad of symptoms that include recurring crops of mouth ulcers (called apthous ulcers), genital ulcers, and uveitis. The ulcers are usually painful. The disease is more frequent and severe in patients from the Eastern Mediterranean and Asia than those of European descent. Eye manifestations may result in blindness. In addition, iritis, retinal vessel occlusions and optic neuritis can be found. Hypopyon uveitis (pus in the anterior chamber of the eye), which is considered the hallmark of Behets disease, is in fact a rare manifestation. CNS vasculitis involvement may lead to TIA, meningoencephalitis, parkinsons and dementia. Vascular thrombosis occurs in about 10% of patients.The arthritis of Behets disease is usually intermittent, self-limited, not deforming and localized to the knees and ankles. A positive pathergy test refers to skin injury by needle prick leads to a papule or pustule formation in 48 hours. Dermatomyositis: Causes proximal muscle weakness, dysphagia and raised muscle enzymes. This is associated with Gottron's papules and also a heliotrope rash around the eye. The condition is associated with carcinoma of the breast, lung, ovary and bowel. Dermatomyositis is most frequent in women, with a male:female ratio of 1:2, and has its peak-incidence in spring and summer. The presence of a rash plus another three or four criterias (proximal and symmetric muscular weakness, elevation of muscular enzymes, inflammatory changes in muscle biopsy or electromyography) confirms the diagnosis. Discoid lupus erythematosus: Lesions are discrete plaques, often erythematous, scaly, with extension into hair follicles. These lesions can occur on the face, scalp, in the pinnae, behind the ears or on the neck. There can also be active indurated erythema and central atrophic scarring. Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints, fevers and rash. The first episode usually occurs by the age of 20 years, but in some cases, the initial attack occurs much later in life. Familial Mediterranean fever primarily affects populations originating from the Mediterranean region, particularly people of Armenian, Arabic, Turkish, and North African Jewish ancestry. A buildup of amyloid proteins occurs in some cases of familial Mediterranean fever and can lead to renal failure if left untreated. AA amyloidosis commonly involves the kidneys, spleen and GI tract. Colchicine given prophylactically in FMF offers some protection against the development of amyloidosis in most patients. Haemochromatosis is associated with chondrocalcinosis, which commonly affects the 2nd and 3rd metacarpophalangeal joints. Hypertrophic osteoarthropathy (or hypertrophic pulmonary osteoarthropathy when there is mesothelioma or bronchogenic carcinoma associated) is associated with conditions such as liver cirrhosis, ulcerative colitis, whipple's disease and crohn's disease.

X rays show periosteal reaction at the ends of the radius and ulnar bones suggestive of periostitis.

Henoch-Schnlein purpura (HSP) is a systemic vasculitis mostly seen in children. It is a multisystem disorder involving the skin, joints, gastrointestinal and renal tracts. Aetiology is unknown, but the syndrome is often preceded by infections such as Group A beta hemolytic streptococcal respiratory tract infection, Campylobacter jejuni, Mycoplasma pneumoniae and viruses such as varicella, hepatitis B, Epstein-Barr virus, and parvovirus B19. Pathology is due to intravascular deposition of IgA immune complexes with activation of complement and leucocyte infiltration. Patients often present with a purpuric rash usually involving the buttocks and lower limbs, arthralgia and joint swelling, severe colicky abdominal pain and tenderness caused by vasculitisinduced thrombosis in the gut. Renal involvement commonly presents as microscopic haematuria and proteinaemia. The most serious long-term complication from HSP is progressive renal failure. Limited cutaneous scleroderma is also known as CREST syndrome (calcinosis, Raynauds, (o)esophageal dysfunction, sclerodactyly, and telangiectasia. Limited refers to the extent of skin involvement limited to the forearms and face. They generally develop pulmonary hypertension rather than pulmonary fibrosis, leading towards breathlessness. Renal hypertensive crisis is more common in diffuse systemic sclerosis and pulmonary hypertension is more common in limited cutaneous scleroderma Polymyalgia Rheumatica A high ESR, shoulder stiffness and pain, age >65, weight loss and depression are features which contribute to diagnostic criteria. There is NO weakness. Muscle enzymes and EMG are typically normal If there is a raised ESR, polymyalgia rheumatica is far more likely than fibromyalgia. 10 mg of prednisolone will suffice for PMR. At the other end of disease spectrum, Giant Cell Arteritis required up to 60 mg of prednisolone to suppress vasculitis Reiters syndrome is urethritis, conjunctivitis, seronegative arthritis (cannot see, cannot pee, cannot climb a tree). The typical patient is a young man with recent urethritis or dysentery. The seronegative arthritis is usually a mono or oligoarthritis. Other features are anterior uveitis, keratoderma blenorrhagica (brown abscesses on palms and soles), mouth ulcers, plantar fasciitis and archilles tendinitis (enthesopathy), circinate balanitis (painless rash) and aortic incompetence. The arthritis may relapse or remain chronic. Management is usually with rest and NSAIDs. Reflex sympathetic dystrophy occurs following trauma to an injured part of the body, and can progress to other parts. It is due to autonomic nervous system dysfunction. Symptoms of extreme pain and burning can occur. Analgesics are often unhelpful. In Paget's disease, onset of symptoms is usually insidious, with pain, stiffness, bone deformity, headaches, decreasing auditory acuity, and increasing skull size.

Signs may be bitemporal skull enlargement with frontal "bossing," dilated scalp veins, nerve deafness in one or both ears, angioid streaks in the fundus of the eye, and anterolateral bowing of the thigh or leg with warmth and periosteal tenderness. Pagetic lesions are metabolically active and highly vascular and may lead to high-output heart failure. Deformities may develop from bowing of the long bones or osteoarthritis of adjacent joints. Pathologic fractures may be the presenting finding. Characteristic x-ray findings include increased bone density, abnormal architecture, cortical thickening, bowing, and overgrowth. Biochemistry includes elevated serum alkaline phosphatase (or bone-specific alkaline phosphatase) and increased urinary excretion of pyridinoline cross-links. Serum calcium and phosphorus levels usually are normal, but serum calcium may increase during bed rest. Potts disease is tuberculous infection of the spine with associated collapse of the vetebral body. Signs and symptoms include: Localised back pain, Paravertebral swelling, Neurological signs including paraplegia. Drug treatment (antituberculous drugs) is generally sufficient for Potts disease, with spinal immobilisation if required. Surgery is required if there is spinal deformity or neurological signs of spinal cord compression. Sarcoidosis: The most common form of joint involvement in sarcoidosis is large joint involvement of lower limb. This is usually a symmetrical oligoarthritis associated wth erythema nodosum and bilateral hilar lymphadenopathy. Sjogrens syndrome: history of dry eyes (keratoconjunctivitis sicca) and joint pains with strongly positive RhF. Ro is also known as anti ssA and La is known as anti ssB antibody, both are diagnostic tests for Sjogrens. Takayasu's arteritis is a large vessel vasculitis of unknown origin. The vasculitic process involves structures such as the aorta, great vessels, the sclera and the cardiac conduction tissues. Women are affected more than men, usually in the second and third decades of life. Presentation is often with symptoms such as fever, weight loss, night sweats and arthralgias. Symptoms related to ischaemia may include ischaemic stroke, visual disturbances and claudication. X-linked hypophosphataemic Vit D resistant rickets, serum phospate is low and urine phosphate is high due to inappropriate renal phosphate wasting. Serum parathyroid levels are usually normal or slightly elevated. Clinically, the most obvious of these aspects is the effect on bone formation and growth that causes very severe rickets, especially in affected males. Treatment is with oral phosphate (difficult to tolerate) and high dose activated Vitamin D.

ANATOMY The axillary nerve supplies the deltoid and teres minor as well as the skin over the deltoid. The ulnar nerve innervates the third and fourth lumbricals, the interossei and adductor pollicis. Sensation is supplied to the fifth finger and the ulnar part of the fourth finger. It also innervates the Interossei- Dorsal: Abductors (DAB) and Palmar: Adductors (PAD). Claw hand is typical of ulnar nerve injury which can be due to pressure palsy around the elbow. This is due to weakness of the small muscles of the hand leading to hyperextension at the MCP and flexion at the interphalangeal joints. A good rule to follow is that the radial nerve supplies the extensors of the Flexion of the fingers and thumb abduction is supplied by the median nerve. Extension of the fingers are supplied by radial nerve. forearm and fingers, not the flexors irregardless of whether it is ulnaris or radialis. Examples are: extensor carpi ulnaris, extensor pollicis longus, supinator. Lesions of the radial nerve in the spiral groove spare the triceps. The lateral two lumbricals, opponens pollicis, abductor pollicis brevis and flexor pollicis brevis are supplied by the median nerve. Flexion of the fingers and thumb abduction is supplied by the median nerve. The fibers of the musculocutaneous nerve originate in the lower cervical spinal cord (usually C5 to C7), travel via the lateral cord of the brachial plexus, and supply sensory and motor innervation to the upper arm, elbow, and forearm. It supplies the biceps which controls elbow flexion. Sensation is to the lateral area (lateral cutaneous nerve) of the forearm. A lesion in the anterior interosseous nerve results in weakness of the terminal phalanges of the thumb and index fingers. Waiter's tip deformity is due to C5 and C6 brachial nerve injury (Duchenne-Erb paralysis). A C5 root lesion causes weakness in abduction of the shoulder and biceps, as well as sensory loss in the upper arm. A C7 root lesion causes weak wrist extensors and flexors, weak finger extensors and sensory loss to middle finger. A T1 lesion causes weak intrinsic hand muscles. The axillary nerve supplies the deltoid and teres minor as well as the skin over the deltoid. The tibial nerve supplies the gastrocnemius muscle. Tibial nerve palsy causes weakness in in knee extension, plantar flexion and foot inversion on the left. He also

is unable to tiptoe on the same foot. Ankle jerk is absent. The tibial nerve carries L4 & L5 roots. The sciatic nerve supplies iliacus, pectineus, sartorius, quadriceps femoris. It supplies cutaneous branches to the front of the thigh. The sciatic nerve is commonly injured by fractures of the pelvis, gunshot wounds, or other trauma to the buttocks or thigh. Injury to the lateral cutaneous nerve of the thigh as it travels under the inguinal ligament can cause numbness and sensory loss to the antero lateral part of the thigh. Foot drop can be caused by damage to the tibial nerve and common peroneal nerve. The obturator nerve supplies gracilis, the adductor (longus, brevis, magnus) and the skin over the lateral aspect of the thigh. Femoral nerve supplies the quadriceps. The common peroneal nerve controls foot eversion and dorsiflexion. Sensation is supplied to the antero-lateral part of the leg and the dorsum of the foot. EPILEPSY Brief episodes of jerking suggests simple partial seizures. Carbamazepine is first line therapy for this. For a single seizure, driving is not permitted for 1 year. An epileptic patient can drive after 1 year of they have been free from any attack, or after 3 years if they have had attacks only during sleep. HGV licence only if seizure free for 10 years. Absence seizures consist of suspension of awareness lasting a few seconds. They occur without warning, are provoked by overbreathing, and are not usually associated with complex motor movements or post-ictal confusion. The characteristic ictal EEG is 3 Hz spike and wave. Complex partial seizures may be preceded by an aura, can be associated with behavioural and cognitive signs. Partial seizures from the temporal lobe typically causes motor movements like grimacing and sucking movements, rotation of the head and eyes. There are other features associated with temporal lobe epilepsy. Dj vu and Jamais vu (unreal perceptions) may occur. Visual, auditory and olfactory hallucinations may occur. An aura may occur, associated with micropsia (distorted visual perception in which objects appear smaller than their actual size) or physicial sensations in the stomach. Carbamazepine and phenytoin are used to treat the condition. Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epileptic syndrome characterized by myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and

sometimes absence seizures. These can be precipitated when sleep deprived. Apart from sodium valproate, lamotrigine and topirimate can also be used. MIGRAINES AND HEADACHES In migraines, beta blockers, calcium channel blockers and antidepressants may be helpful in prophylaxis. Cluster headaches: Verapamil, prednisolone, prochlorperazine, lithium carbonate, ergotamine and methysergide can help to prevent these. Third nerve palsy leads to ptosis, dilated unreactive pupil and eye looking down and out. The afferent pathway is controlled by the optic nerve and the efferent pathway by the oculomotor nerve - hence a dilated poorly reacting pupil. IIIrd nerve palsy causes: Neurosyphillis / meningovascular syphillis Diabetes Mellitus Myasthenia gravis Opthalmic migraine Syphillis causes Argyll Robertson pupil - small and iregular pupils which do not react to light because they are already small. [mnemonic: ARP: Accomodation Reflex Present, PRA: Pupillary Reflex Absent] Dilated pupils occur in IIIrd nerve palsy and Holmes Adie pupil. Holmes Adie is also called a myotonic pupil due to the slow reaction and is ssociated with diminished tendon reflexes. A Holmes Adie pupil is a large pupil, unresponsive to light. Marcus Gunn pupil is an afferent pupillary defect thus pupils do not constrict. The pathway of the pupillary light reflex consists of: retinal receptor cells, bipolar cells, ganglion cells, optic nerve and tract, lateral geniculate bodies, superior colliculus and pretectal nucleus of the high midbrain, Edinger-Westphal nucleus, efferent two neurone pathway via the oculomotor nerve (IIIrd nerve), ciliary ganglion, constrictor muscle of the iris. Superior quandrantinopia is seen in damage to the temporal part of optic radiation lesions. Inferior quandrantinopia is seen in damage to the parietal part of optic radiation lesions Bitemporal hemianopia is seen in optic chiasmic lesions. Central scotoma is usually caused by lesions between the optic nerve and chiasm Causes of Central Scotoma Hereditary familial optic atrophy Syphillitic optic atrophy

 Papilloedema Retrobulbar neuritis Internuclear opthalmoplegia: The medial longitudinal fasciculus (MLF) connects the sixth nerve and third nerve to the Paramedian Pontine Reticular Formation. There is nystagmus in the abducting eye (mnemonic NAB) and limited movement in the adducting eye on the same side. Upward gaze is not affected. Internuclear opthalmoplegia can be caused by: Multiple Sclerosis stroke (basilar artery) encephalitis syphilis lyme disease phenothiazines tricyclic antidepressants Causes of optic neuritis: Sarcoid Multiple sclerosis drugs (ethambutol) infections (syphillis, CMV, brucella, toxoplasmosis) Causes of papilloedema: Intracerebral haemorrhage central retinal vein thrombosis venous sinus thrombosis benign intracranial hypertension The lateral gaze centre is situated in the pons. A lesion in the right pons will cause impaired conjugate gaze to the right side, with consequent deviation away from the right side. CEREBROVASCULAR DISEASES AND VARIOUS BRAIN STEM DISORDERS Brocas Area (Inferior frontal lobe) damage causes impaired fluency, intact comprehension, impaired repetition [expressive dysphasia]. Wernickes Area (posterior, superior temporal lobe) damage causes normal fluency, impaired comprehension, impaired repetition [receptive dysphasia]. The cingulate gyrus forms part of the limbic system, which is associated with mood and emotions. Caudate nucleus, putamen and globus pallidus are areas within the basal ganglia which, when impaired, can lead to choreiform movements.

Medial medullary syndrome is caused by an ipsilateral 12th nerve lesion (tongue paralysis) and contralateral weakness and loss of postural sense due to lesions in the pyramidal tract and the medial leminiscus. Lateral medullary syndrome: Multiple areas are involved : 9th and 10th nerve - dysphagia and dysarthria Nucleus ambiguus - vomiting and hiccup Vestibular nuclei - vertigo Inferior cerebellar peduncle ipsilateral cerebellar ataxia Descending autonomic fibres - Horners syndrome Fifth nerve nucleus - loss of pain and temperature sensation over the face (ipsilateral) Lateral leminiscus - loss of pain and temperature sensation in the contralateral limbs The posterior cerebral artery supplies the occipital lobe and occlusion causes damage to the visual cortex, resulting in homonymous hemianopia. There are many parietal lobe signs. These include : loss of two point discrimination agraphia agnosia astereognosis dyslexia Gerstmann syndrome receptive dysphasia dressing and constructional dyspraxia Dystonic posturing can be related to temporal lobe epilepsy. Gerstmann syndrome includes four features (acalculia, agraphia, finger agnosia, left right disorientation), and is due to a lesion in the dominant hemisphere. In a right handed patient, the left hemisphere is dominant. In a lesion of the superior colliculus (mid-brain) there may be damage to the IIIrd nerve nucleus and cerebral peduncles, leading to a third nerve palsy and contralateral hemiparesis. MYASTHENIA In Lambert Eaton myasthenic syndrome, 60% of cases are paraneoplastic (small cell lung ca is most associated). The clinical features are proximal weakness, loss of tendon reflexes and autonomic dysfunction. Myasthenia gravis can be differentiated from Eaton Lambert myasthenic syndrome by electromyography. Repetitive stimulation in myasthenia gravis leads to a decrement of evoked muscle action potentials, whilst in myasthenic syndrome the condition improves by repetitive stimulation. Also, in myasthenia gravis the tendon reflexes are characteristically normal. If the reflexes are depressed, Eaton-Lambert syndrome should be considered.

Pyridostigmine is an anticholinesterase which reduces acetylcholine breakdown and hence improve symptoms of fatiguability in myasthenia gravis. In myasthenia gravis, there are positive anti-Ach antibodies. Thymectomy improves the prognosis in patients below 40 years and in those with positive receptor antibodies. Following thymectomy, 60 % of patients will improve. Thymectomy is usually recommended because of the risk of malignancy. The list of drugs which may make myasthenia worse are: erythromycin streptomycin ampicillin Verapamil propranolol Aminoglycosides Quinidine Procainamide Magnesium Lithium Phenytoin chlorpromazine clozapine PARKINSONS Causes of parkinsonism are: Drugs - Reserpine, tetrabenazine, Phenothiazines Toxins methyl-phenyl-tetrahydropyridine, Manganese, Carbon monoxide, Viral - Encephalitis, eg. Japanese B, Neurone damage - Supra nuclear palsy, Shy Drager syndrome (Multi system atrophy), Cerebral tumour, Wilsons disease, Huntingtons disease, Neurosyphillis Parkinsons Therapy Co-careldopa (contains L dopa) is the first medication used to increase dopaminergic activity in the basal ganglia. Side effects are dyskinesia, postural hypotension, nausea. Benztropine is used for anticholinergic side effects. Selegiline is an MAO inhibitor (potentiates dopamine) Amantadine is an antiviral drug (also potentiates dopamine) used as a second line drug. Apomorphine is used for on-off fluctuations. Benzhexol is indicated when there is mild parkinsonism or when there is oculogyric crisis. Sterotactic surgery is indicated when there are unilateral symptoms. Ropinirole is a dopamine 2 agonist, In progressive supranuclear palsy (PSP), early onset of postural instability and vertical gaze palsy. However, a reduction in upgaze is non-specific as it may be present in a number of other conditions or even normal ageing. Other features of PSP include very reduced blinking, which may lead to dry eye and conjunctivitis.

Retrocollis and frontalis over activity, which leads to a startled expression. The akinesia is usually symmetrical from its onset. MUSCLE DISEASES Mutation in the dystrophin gene causes deficiency of dystrophin in Duchenne's muscular dystrophy. Patients develop progressive upper and lower limb weakness with pseudohypertrophy of calves and quadriceps. Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy. It is of autosomal dominant inheritance. Onset is usually age 20 years. Initial weakness is seen in facial muscles, starting in the orbicularis oculi, orbicularis oris, and zygomaticus. Shoulder weakness is the presenting symptom in more than 82% of patients. Winging of the scapula is the most characteristic sign. Creatine kinase levels are raised. The drug Albuterol which relaxes bronchial smooth muscle has been shown to increase lean muscle mass when used over a period of months. Myotonic dystrophy is autosomal dominant. It is a trinucleotide repeat disorder which exhibits anticipation (worse with successive generations). Associated features are cataracts, diabetes, testicular atrophy and cardiac conduction abnormalities, cardiomyopathy, dysphagia, cognitive impairment. Spinal muscular atrophies are a group of disorders characterised by progressive degeneration of the motor neurons of the spinal cord and brainstem. Muscles weaken and atrophy due to degeneration of motor neurones which are nerve cells in the spinal cord. In general we can distinguish three common types of SMA in childhood : Type 1 Severe Infantile SMA, or Werdnig-Hoffmann disease, Type 2 Intermediate type, Type 3 Mild Juvenile SMA, or Kugelberg-Welander disease. Most forms, especially the earlier onset, are inherited in an autosomal recessive manner. Creatinine kinase is normal, although EMG may show fibrillations secondary to denervation. This also produces group atrophy on muscle biopsy. There are no treatments, and prognosis depends on the severity of the form. CEREBELLAR SYNDROMES The tremors in cerebellar syndrome are 3Hz, whilst the tremors in essential tremor are 5-8Hz. Spinocerebellar Ataxia: SCA 1 is purely cerebellar, whilst other forms may have eye involvement or areflexia. Friedreich's Ataxia is an autosomal recessively inherited. It is multisystemic. Outside neurological abnormalities, patients may have cardiomyopathy and diabetes.

Neurological abnormalities include optic atrophy and retinitis pigmentosa, nystagmus, cerebellar disease and signs, loss of dorsal column sensation and weakness. Pes cavus (high arched feet) is usually present. Anti Yo antibodies are associated with a cerebellar syndrome due to either lung, breast or ovarian carcinoma. A mnemonic for cerebellar signs is VANISHD Vertigo, Ataxia, Nystagmus, Intention tremor, Scanning speech, Hypotonia and Dysdiadochokinesis. MITOCHONDRIAL MYOPATHIES Chronic progressive external ophthalmoplegia (CPEO) is a disorder characterized by slowly progressive paralysis of the extraocular muscles. Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later. Leber's Hereditary Optic Neuropathy is a rare condition which can cause loss of central vision. It usually affects men, most commonly in the late twenties or early thirties, but the symptoms can happen at any age, to men or women. MELAS (myopathy, encephalopathy, lactic acidosis and stroke like episodes). Lactic acidosis is a very important feature of this disorder, as measured by a high lactate to pyruvate ratio. However, in general, lactic acidosis does not lead to systemic metabolic acidosis, and it may be absent in patients with impressive involvement of the central nervous system. Patients have a myopathy causing proximal muscle weakness and hypotonia, seizures and strokelike episodes. It is a mitochondrial inherited disorder. MERRF (myoclonic epilepsy, ragged red fibres). The most characteristic symptom of MERRF syndrome is myoclonic seizures that are usually sudden, brief, jerking, spasms that can affect the limbs or the entire body. Ataxia as well as lactic acidosis may also be present in affected individuals. Dysarthria, optic atrophy, short stature, hearing loss, dementia and nystagmus may also occur. MOVEMENT DISORDERS The following features support a diagnosis of Essential Tremor: (1) bilateral action tremor of the hands and forearms (2) absence of other neurological signs, except the cogwheel phenomenon (3) may have isolated head tremor with no signs of dystonia Secondary criteria include a long disease duration (more than three years), a positive family history and beneficial response to alcohol. Discomfort in the arms and legs, arm or leg restlessness, relief with movement and worsening symptoms in the evening are features that satisfy diagnostic criteria of restless leg syndrome. It is associated with Parkinsonism, iron deficiency anaemia, diabetes mellitus and hypothyroidism.

Hemiballismus is a rare disorder characterised by involuntary wild flinging movements of the limbs. It is usually unilateral (hence hemiballismus) and is caused by lesions in the contralateral subthalamic nucleus. Catalepsy (a form of catatonia) is a disorder of muscle tone in which uncomfortable positions can be maintained for a long time. It is a feature of schizophrenia. Cataplexy is the sudden loss of motor tone associated with the sleep disorder narcolepsy. Chorea Huntington's disease, carbon monoxide poisoning, Behcet's disease and DRPLA are causes of chorea. Huntington's disease is usually autosomal dominant. It is a trinucleotide repeat disorder involving CAG repeats. The gene is mapped to chromosome 4 (remember GABA 4 letters). There is an increase in the protein Huntingtin (polyglutamine), because glutamine is coded for by CAG. Anticipation refers to the increase in severity with subsequent generations. Patients with Huntington's disease have dementia, ataxia, abnormal choreiform movements and opthalmoplegia. A small percentage of children present with a parkinsonian like akinetic rigid syndrome or epilepsy. Treatment is with phenothiazines (haloperidol) for symptomatic control. Sydenhams chorea is the least common presentation of acute rheumatic fever (3% of patients). It is mostly observed in young girls and presents as involuntary choreoathetoid movements of face, tongue and upper extremities. MULTIPLE SCLEROSIS 80% - Relapsing / remitting short attacks of relapses (4-6 weeks) - 1/3 of these patients become secondary progressives 20% - Primary progressive gradual deterioration from onset Diagnosis - Demyelination seen on MRI, gadolinium enhancing l4sions Delayed Visual Evoked Potentials CSF oligoclonal bands present (not in the serum) Presentation - Optic neuritis painsful visual loss, colour vision affected Spastic paraparesis Urinary retention or incontinence (may need self catheterisation) Therapy iv methylprednisolone for relapses (500mg for 3 or 5 days) - B interferon subcutaneous injection 1x a week only for relapsing remitting MISCELLANEOUS Absent tendon reflexes and extensor plantars point towards a combined UMN and LMN lesion.

The causes of extensor plantars (UMN) and absent ankle jerks (LMN) are: Motor neuron disease Subacute combined degeneration of the cord (B12 deficiency) Tabes Dorsalis (syphilis) Lesion of the cauda equine Diabetes+CVA Friedriechs ataxia Arnold-Chiari Malformation is a condition in which the cerebellum portion of the brain protrudes into the spinal canal. It may or may not be apparent at birth. Arnold-Chiari I type malformation usually causes symptoms in young adults and is often associated with syringomyelia, in which a tubular cavity develops within the spinal cord. Arnold-Chiari II type malformation is associated with myelomeningocele (a defect of the spine) and hydrocephalus (increased cerebrospinal fluid and pressure within the brain). Benign intracranial hypertension is most common in women between the ages of 20 and 50. BIH is likely due to high pressure caused by the buildup or poor absorption of cerebrospinal fluid in the subarachnoid space surrounding the brain. Symptoms include headache, nausea, vomiting, and pulsating intracranial noises, closely mimic symptoms of brain tumors. Vitamin A, prednisolone, minocycline and cyclosporin make benign intracranial hypertension worse. Acetazolamide is used to treat BIH. Botulism is a paralytic disease caused by the neurotoxins of Clostridium botulinum and in rare cases, Clostridium butyricum and Clostridium baratii. Wound botulism, caused by systemic spread of toxin produced by organisms inhabiting wounds, is associated with trauma, surgery, subcutaneous heroin injection, and sinusitis from intranasal cocaine abuse. The neurologic symptomatology often has been described as a progressive, symmetric, descending weakness or paralysis that first affects muscles innervated by the cranial nerves, then progresses to involve muscles of the neck, arms, and legs. Respiratory difficulty arises from airway obstruction and diaphragmatic weakness. Diplopia, dysarthria, dry mouth, and generalized weakness are among the most common presenting symptoms. The botulinum toxin assay can be done to confirm the diagnosis Brown Sequard syndrome which describes hemisection of the spinal cord, causes ipsilateral UMN signs and proprioception loss, and contralateral sensory loss. Causes of Upper Motor Neuron facial weakness CVA pontine haemorrhage Multiple Sclerosis motor neuron disease Causes of Lower Motor Neuron facial weakness : Sarcoidosis

infective polyneuritis Lyme disease poliomyelitis Guillan-Barre Syndrome vasculitis HIV Causes of lymphocytic meningitis : TB, HSV, mumps, HIV, enteroviruses, Brucella and Listeria EMG Reduced amplitude and duration of motor units changes are consistent with a myositis. In motor neuron disease, fibrillation is seen. In myasthenia, there is diminished response to repetitive stimulation. Reduced amplitude of action potential is seen in axonal neuropathy. Reduced conduction velocity or conduction block is seen in demyelination. In myotonia, an extended series of repetitive discharges lasting up to 30 seconds occurs. New variant CJD commonly presents in young adults painful sensory symptoms in the lower limbs and also psychiatric symptoms. Cognitive impairment, pyramidal signs, myoclonus and primitive reflexes then develop. MRI commonly shows high signal on T2-weighted images in the pulvinar (posterior aspect of thalamus). EEG is often normal, unlike sporadic CJD, in which triphasic waves are observed. In sporadic CJD, the EEG changes usually show diffuse, non-specific slowing (1-2 Hz) and sharp wave complexes, in deep brain areas (thalamus). A very rare condition associated with Hashimoto's Thyroiditis is Hashimoto's Encephalopathy. In Hashimoto's Encephalopathy, antibodies attack the neurons in the brain. Some of the common symptoms include: disorientation, psychosis, tremors, concentration and memory problems, jerks in the muscles and lack of coordination, headaches, partial paralysis on the right side, and speech defects. The main treatment is prednisolone. In HSV encephalitis, there can be disorientation or dysphasia and seizures. There is also mild lymphocytosis on the CSF. MRI may show frontal or temporal lobe involvement. EEG may show periodic sharp wave activity temporally and background of focal or diffuse slowing. Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the CNS that seems to be immune mediated. It may be precipitated by measles, rubella, Varicellazoster, smallpox, mumps, influenza, parainfluenza, infectious mononucleosis, typhoid, mycoplasma infections. PML, CNS lymphoma, encephalitis (HSV, CMV), cerebral toxoplasmosis and cerebral TB are AIDS related.

HMSN 1 is the most common form of hereditary neuropathy. Severely and uniformly slowed nerve conduction velocities (NCVs) and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes are the hallmarks of the disease. Motor symptoms predominate over sensory symptoms. Often, patients report loss of balance, muscle weakness, and foot deformities. Onset in the first decade of life is typical, but disease develops in some patients in young or mid adulthood. HMSN 2, on the other hand, represents the nondemyelinating neuronal type with relatively normal NCVs and primary axonal pathology. Although nerves are not enlarged in the neuronal form, weakness often is less marked and onset of this neuropathy is delayed. Peripheral nerves are not enlarged clinically, and weakness of feet and leg muscles predominates; hands are less severely affected than the legs. Patients experience sensory loss in the distal extremities, and foot deformities (ie, pes cavus) tend to be less marked than those of HMSN 1. Hereditary spastic paraparesis often classified based upon whether progressive spasticity occurs as an isolated finding (i.e., uncomplicated or "pure" HSP) or with other neurologic abnormalities (i.e., complicated HSP). In families affected by complicated HSP, associated neurologic features have included mental retardation; deafness; degenerative changes of the retinas or the nerve-rich, innermost membranes of the eyes (retinopathy); impaired coordination of voluntary movements (ataxia); or progressive deterioration of thought processing and acquired intellectual abilities (dementia). HSP may be inherited as an autosomal dominant, autosomal recessive, or x-linked recessive trait but the commonest form of inheritance is autosomal dominant. Glioblastoma multiforme is by far the most common and most malignant of the glial tumors. Composed of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the cerebral hemispheres. Glioblastoma is commoner in adults than medulloblastoma. Although current therapies remain palliative, they have been shown to prolong quality survival. Without therapy, patients with GBMs uniformly die within 3 months. Patients treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 1 year. Guillain Barre syndrome is preceded by diarrhoea (e.g. campylobacter) and chest infections (e.g. mycoplasma) in two thirds of cases. Autonomic dysfunction and hyporeflexia re associated. Studies have shown that plasma exchange and IVIg are equally effective in treating people within two to four weeks of onset of GBS. Inclusion body myositis: In this condition, dysphagia and respiratory involvement can also occur. Muscle biopsy shows intracellular inclusions (amyloid precursor protein, ubiquitins) and inflammatory infiltrates. Clinical suspicion for s-IBM should be very high when the pattern of weakness affects

(1) the finger/wrist flexors out of proportion to the finger/wrist extensors and shoulder abductors or (2) knee extensors disproportionate to the hip flexors. Dysphagia may occur in up to 40% of patients and is secondary to direct involvement of the cricopharyngeal musculature. Kennedy's syndrome is an X linked recessive (spino-bulbar muscular atrophy), trinucleotide repeat disorder. There is peri-oral and tongue fasciculation, facial weakness, proximal limb weakness, limb fasciculation and dysarthria. CK is often elevated, and there may be gynaecomastia and testicular atrophy. Multifocal motor neuropathy: There is lower motor neuron muscle weakness, typically in the legs. Anti-GM1 antibody and NP-9 antigen are present in multifocal motor neuropathy. Motor conduction block is also seen in multifocal motor neuropathy. Normal pressure hydrocephalus (NPH) is a clinical symptom complex characterized by abnormal gait, urinary incontinence, and dementia. Ventricular enlargement out of proportion to sulcal atrophy on the CT scan. Surgical CSF shunting remains the main treatment modality. Narcolepsy Hypnogogic and hypnopompic hallucinations are seen in narcolepsy. Episodes of cataplexy occur. The HLA association is DQB1, Clomipramine is a tricyclic antidepressant which may help, there is early REM sleep and hypnagogic hallucinations occur. Neuroacanthocytosis is diagnosed by the demonstration of acanthocytes on the peripheral blood film. It is a progressive neurologic disease characterized by movement disorders, personality changes, cognitive deterioration, axonal neuropathy, and seizures. Horner's syndrome. The sympathetic nerve fibres from the hypothalamus travel through brainstem and cervical cord to T1/T2. These synapse on preganglionic sympathetic fibres, travel up sympathetic chain to superior cervical ganglion, and then synapse onto postganglionic fibres which travel with common and internal carotid arteries. Neurofibromatosis NF1 (NF gene 1 defect) is found on chromosome 17 (mnemonic: there are 17 letters in the word). NF2 gene defect is on chromosome 22. Lisch nodules (pigmented spots) of the iris are present in more than 90% of patients with neurofibromatosis type 1. The diagnosis is suggested by six or more caf au lait spots. Although the condition is autosomal dominant, almost half of all cases are new mutations. Bilateral acoustic neuromas are a hallmark feature of neurofibromatosis type 2

In motor neuron disease, UMN signs include muscle spasticity, slowed recruitment of voluntary muscle strength, weakness especially in the extensors of the upper limb and flexors of the lower limb muscles, pseudobulbar palsy. LMN features include muscle wasting and fasciculation, depressed reflexes and bulbar palsy. Onset of the disease is usually in mid to late adult life with the incidence increasing with advancing age. Paraneoplastic syndrome. Anti Yo antibodies are found in around half of all patients with paraneoplastic cerebellar degeneration. Associated with small cell carcinoma, ovarian tumours and Hodgkins lymphoma. Anti Hu antibodies are associated with small cell carcinoma of the lung. It is usually associated with sensory neuropathy or with encephalomyelitis. Pellagra: A triad of dementia, diarrhoea and dermatitis. Niacin (nicotinamide or nicotinic acid) deficiency causes pellagra only if tryptophan, an amino acid, is also deficient. Encephalopathy usually follows. It is characterized by confusion, disorientation, hallucinations, and memory loss. Subacute Combined Degeneration of the cord: Vitamin B12 deficiency causes ataxia, posterior column cord damage (Loss of vibration sense and proprioception), spasticity, extensor plantars and neuropsychiatric symptoms. Pain is controlled by the spinothalamic tracts which are not affected in B12 deficiency. Syringomyelia is chronic disorder characterised by the presence of glial-lined cavities situated in the central part of the spinal cord. Recognised causes include Chiari type I malformation, central cord tumours, basal arachnoiditis and trauma. There may be sensory loss, wasting of the small hand muscles, uni- or bilateral Horners syndrome, abnormalities of sweating, thickening of subcutaneous tissues, atrophy and decalcification of bones, development of Charcots joints and Chiari I malformation (due to arachnoiditis). Tuberous sclerosis. This is an inherited (autosomal dominant) hamartomatous condition in which there are facial angiomas (adenoma sebaceum), subungual fibromas, angiomyolipomas, cardiac rhabdomyomas, pulmonary lymphatic involvement, skin changes such as shagreen patches and ashleaf macules. Acoustic neuromas are associated with neurofibromatosis type 2 and not tuberous sclerosis. von Hippel Lindau disease is associated with cerebellar haemiangioblastomas and retinal angiomas and polycystic liver or kidneys. Ectopic erythropoietin secretion by the haemangioblastomas cause polycythaemia.

DEPRESSION The biological features of depression are lethargy, diurnal variation in mood, early morning waking, loss of appetite, constipation, amenorrhoea, low libido. Psychomotor retardation and variation in mood suggests probably response to TCA. Depression is commoner in women and in urban areas. The findings of the vulnerability factors are only applicable to depression. They were studied by Brown and Harris in a female population. Children under the age of 14, young adolescents, lack of a confidant and lack of employment outside the home were identified as a risk factor. Severe depression (melancholia) is the most frequent indication for ECT. Patients with this illness experience sadness and despair, have difficulty concentrating, lose appetite and weight, sleep poorly, blame themselves, are unable to enjoy life, and often think of suicide. Some patients develop partial loss of memory events over weeks following ECT. Other hazardous effects are cardiac arrhythmia and minor musculoskeletal trauma during anaesthesia. Fluoxetine and venlafaxine are good for patients with psychomotor retardation. Antidepressants should continue for several months. In patients with recurrent relapses, antidepressants should be continued indefinitely. The suicide risk can increase early in antidepressant therapy. BIPOLAR DISORDER Bipolar disorder is equally common in men and women. Symptoms are evident before age 30 years. In bipolar disorder, there is an inherited abnormality in lithium transport in red blood cells and levels or noradrenaline are often elevated. Lithium is used for prophylaxis in bipolar disorder. Pressure of speech and flight of ideas (quick succession of thoughts) occurs in mania. In addition, speech rhyming and clanging (words chosen for sound and not meaning - I ate food, rude, stood) are also important suggestive features. Persistent mood elevation with occasional irritability is typical of hypomania. Hypomania is a mild form of mania, and can occur in bipolar disorder. Olanzepine or benzodiazepines are more effective during episodes of hypomania.

SChizophrenia First Rank Symptoms of Schizophrenia are: Auditory hallucinations third person, thought echo Thought disorder thought withdrawal, insertion or broadcast Passivity experiences actions under external control Delusional perception Acute schizophrenia include lack of insight, delusions of reference, blunt affect, auditory hallucinations, Olfactory or gustatory hallucinations, delusional mood, persecutory delusions, suspiciousness, hostility, social withdrawal and thought echo. Thought broadcast is an example of thought alienation. This suggests a psychotic disorder. Other forms of thought alienation are thought withdrawal and thought insertion. Depersonalisation (person feels unreal) and derealisation (environment feels unreal) are present not only in psychotic disorders, but also anxiety states and depression. Poor prognostic features of schizophrenia are: strong family history early age of onset insidious onset negative symptoms (blunted affect, emotional withdrawal, apatheticness, social withdrawal, lack of spontaneity) street drug use. Good prognostic features are : acute onset early treatment good response to treatment female sex good social adjustment The positive symptoms of schizophrenia include: hallucinations formal thought disorder delusions bizarre behaviour The negative symptoms of schizophrenia include poverty of speech (alogia) poor motivation (avolition) inability to derive pleasure (anhedonia) emotional blunting attentional deficit There is higher incidence of schizophrenia among those with unstable relationships e.g. separated individuals. It is also commoner among patients with low social class. There is higher risk of one twin being affected if the other is.

OTHER PSYCHOSIS Paraphrenia is a schizophrenia like psychosis which occurs in the elderly. Haloperidol and trifluoperazine are examples of older generation antipsychotics which have parkinsonian side effects. New generation antipsychotics: risperidone, olanzepine, quetiapine, clozapine, zotepine In schizoaffective disorder, antipsychotics such as clozapine, haloperidol, and quetiapine, are used for the schizo component. Valproate, carbamazepine and fluoxetine are sometimes used for the affective component. Puerperal psychosis is more common in the first pregnancy (primigravada). The rate is 1 in 500. The onset is usually acute. The prognosis is good, recurrence rate of puerperal psychosis is 14-20%. Treatment is with antipsychotics (be cautious of breast feeding) or ECT. Korsakoffs psychosis is typically associated with short term memory loss and then confabulation by patient when he is unable to accurately describe something. PHOBIAS Anxiety: Symptoms associated with anxiety are: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. Agoraphobia produces intense anxiety when the person is in a place where escape is difficult or embarassing. Those people who have had panic attacks often worry about being in a place where help may not be available, if they have another attack. One of the characteristic features of panic disorder is the fear that something drastic is going to happen during an attack, e.g. impending doom. The episode usually lasts for several minutes, and the patient may react with fear or try to escape the situation. DEMENTIA The combination of progressive cognitive decline, fluctuating symptoms, visual hallucinations, extrapyramidal signs (rigidity and bradykinesia more prominent than tremor) suggest Lewy body dementia. It is progressive. Patients are at risk of falls and syncope. Symptoms and signs of DLB probably result in part from disruption of information flow from the striatum to the neocortex, especially the frontal lobe. The cause is multifactorial. Altered neuromodulator and/or neurotransmitter levels (eg, acetylcholine, dopamine) influence the function of many neuronal circuits. In Alzheimer's, senile plaques, neurofibrillary tangles are seen throughout the cerebral cortex. The distinction between senile dementia and Alzheimers is unclear. Some forms of Alzheimers are familial with Amyloid Precursor Protein mutations. Depressive pseudodementia forms of Alzheimer's occur.

Patients with pseudodementia related to depression usually have global memory loss, whilst patients with dementia have shorter term memory loss. Those with pseudodementia may give a detailed history but still perform badly on tests. Patients with pseudodementia make poor effort, but may score much better when successful in memory testing. Patients with dementia will have a low score. In pseudodementia, patients indicate depression directly when asked. Other clues include patients having the ability to pinpoint the onset of symptoms and give detailed accounts of their impairments. Long term (remote) memory may be sketchy in pseudodementia when interviewed, unlike other dementias where long term memory is relatively intact. Treatment is directed at the underlying depression in pseudodementia. ANOREXIA AND BULIMIA Features of anorexia nervosa are lanugo hair (fine hair on the back, arms and face), mpaired temperature regulation, and sleep deficiencies. Metabolic effects in anorexia nervosa include metabolic alkalosis, elevated plasma amylase, hypercholesterolaemia, hypoglycaemia, high cortisol, hyponatraemia and hypokalaemia, impaired glucose tolerance, beta-hydroxybutyric acid increase, protein deficiency, increased carotene, zinc deficiency. Bulimia is diagnosed by recurrent binge episodes. There is compensatory behaviour to prevent weight gain after a binge episode. This may be in the form of laxative abuse, induced vomiting or overexercise. MISCELLANEOUS Anger, guilt, denial, acceptance and anxiety are features which can occur following the breaking of bad news. The criteria for chronic fatigue syndrome are : 1) severe chronic fatigue of six months longer duration 2) Have four more of following symptoms: substantial impairment in short-term memory poor concentration sore throat tender lymph nodes muscle pain multi-joint pain without swelling redness headaches of a new type pattern severity unrefreshing sleep post-exertional malaise lasting more than 24 hours Low dose antidepressants are used in treatment of CFS, but suggested first line therapy should include cognitive behavioural therapy.

Dissociative amnesia is a psychogenic disorder where there is no organic reason for memory loss. Fluctuating levels of good and bad memory particularly suggest dissociative amnesia. Delirium or acute confusional state is a transient global disorder of cognition. Delirium is defined as a transient, usually reversible, cause of cerebral dysfunction and manifests clinically with a wide range of neuropsychiatric abnormalities. Patients with delirium who are hyperactive have an increased state of arousal, psychomotor abnormalities (ie impaired basic motor or psychological functions), and hypervigilance. Other symptoms are clouding of consciousness, Disturbance of consciousness, Change in cognition (eg, memory deficit, disorientation, language disturbance, perceptual disturbance). Delirium is acute, has altered consciousness and psychomotor changes. Dementia is progressive, there is clear consciousness and psychomotor function is normal. Dermatitis artefacta is a condition in which skin lesions are solely produced or inflicted by the patient's own actions. This usually occurs as a result or manifestation of a psychological problem. It could be a form of emotional release in situations of distress or part of an attention seeking behaviour. The predominant feature is a ritual which is unreasonable, but essentially unstoppable for a person who has obsessive compulsive disorder. Aggression is uncommon, and patients often have associated depression. Obsessional doubts, rituals, thoughts (rumination) and even slowness occur. An obsessional impulse is a strong inclination for the patient to harm or do something dangerous. Frontal lobe damage patients present with poor memory, sometimes referred to as "forgetting to remember." The thinking of patients with frontal lobe injury tends to be concrete, and they may show perseveration and stereotypy of their responses. Perseveration is the act of persisting; continuing or repeating behavior. This can be associated with difficulties in planning or executing action. Frontal lobe changes also include personality change, disinhibition, euphoria, apathy, aphasia, reduced activity, lack of drive, inability to plan ahead, and lack of concern. Transient Global Amnesia or TGA is a sudden failure of memory, affecting older adults. The attack lasts for hours, sometimes a whole day. In many cases (up to a third), TGA is preceded by physical or emotional stress, for example hot baths, cold swims, rushing around and personal dramas. Sex has frequently been implicated as well. A person with TGA is disorientated and upset, though physically well. They can think and communicate, but forget what time it is or where they are - responding to something intelligently but after about a minute forgetting. Despite patchy memory loss about the recent past, distant memories remain. The lost memories come back, but events that took place during TGA are never recalled. The underlying cause is proposed to be vascular insufficiency to the memory areas hippocampi.

Grief reaction causes symptoms of decrease in appetite, weight loss, ruminations, troubled sleep, distractability, thoughts about dying, and impaired concentration. Symptoms last for up to 6 months. Feelings of hopelessness, guilt and worthlessness may signify depression rather than grief reaction. There is a difference between malingering and Munchausen's syndrome. Malingering patients have a clear secondary gain, whilst there is no convincing secondary gain in Munchausen's syndrome (occasionally said to be due to attention seeking behaviour). Post traumatic stress disorder is a delayed and/or protracted response to an exceptionally stressful event. Symptoms include episodes of reliving the trauma, avoidance behaviour, persistent numbness, detachment from people. Parasuicide is a non-habitual act with a non-fatal outcome. Suicide is an act with a fatal outcome. Parasuicide is most common in females, whilst suicide is most common in males. Parasuicide is commonest in social class 5, whilst suicide is commonest in social class 1. The characteristics of patients who are likely to have repeated or successful suicide attempts are: male sex, age of 45 more, drugs, alcohol, personality disorder, living alone (divorced or widowed), criminal record, previous history of psychiatric treatment, lower social class and unemployment. Somatisation is non organic. There are many symptoms which can manifest in somatisation disorder. Mutism is one of the symptoms of which may be present in pervasive refusal syndrome, but without other forms of refusal (e.g. refusal to eat) this diagnosis is unlikely.

BLOOD FILM Target cells are red cells with central staining with precipitated haemoglobin seen in conditions with abnormal haemoglobin as well as cell membrane. Causes of target cells are: Sickle cell disease thalassaemia iron deficiency anaemia liver disease Howell Jolly bodies contain nuclear remnants. Causes are: Post splenectomy Leukaemia Megaloblastic anaemia Iron deficiency anaemia Heinz bodies are precipitated, denatured Hb within red cells. They are also present in G6PD deficiency. (Fava beans cause haemolysis in G6PD - 'Beans means Heinz' mnemonic).

Leuco erythroblastic picture is due to extensive infiltration of bone and may be seen in malignancies like lung cancer metastases, myeloproliferative disorders, severe vitamin deficiency and severe infections. White cell and red cell precursors are found in the bloodstream in leucoerythroblastic picture. Reactive lymphocytes are caused by Ebstein Barr virus infection / infectious mononucleosis CMV infection toxoplasmosis HIV The direct antiglobulin test (Coomb's) is positive if there is autoimmune haemolytic anaemia. It is used to detect IgG or C3 bound to the surface of the red cell. Immune causes of hemolysis including autoimmune hemolytic anemias, drug induced hemolysis, and delayed or acute hemolytic transfusion reactions are characterized by a positive DAT. The red blood cell enzyme assay is a device used to measure the activity in red blood cells of clinically important enzymatic reactions and their products, such as pyruvate kinase or 2,3-diphosphoglycerate. A red blood cell enzyme assay is used to determine the enzyme defects responsible for a patient`s hereditary hemolytic anemia. Sickle cell disease is due to substitution of valine for glutamic acid (position 6 of the beta chain). All forms of sickle cell include HbS. Aseptic necrosis of the hip, cholecystitis, renal papillary necrosis and proliferative retinopathy are clinical features of sickle cell disease. Hb SS patients sickle at 6 kPA hypoxia but SC patients at a lower pO2 of 4 kPa. When there is neurological damage or visceral sequestration crisis in sickle cell crisis, exchange transfusion is indicated. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done manually or automatically with erythrocytapheresis. The acute chest syndrome in sickle cell disease can be defined as: 1. a new infiltrate on chest x-ray 2. associated with one or more NEW symptoms: fever, cough, sputum production, dyspnea, or hypoxia. The most common cause of aplastic crisis, is parvovirus infection. Patients with sickle cell anemia also exhibit increased susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Staphylococcus aureus, and Escherichia coli. THALASSEMIA Mutations in globin genes cause thalassemias. Alpha thalassemia affects the alphaglobin gene(s). Beta thalassemia affects one or both of the beta-globin genes. The genetic defect usually is a missense or nonsense mutation in the beta-globin gene (not deletion). thalassemia is caused by mutations of the globin gene on chromosome 11. In beta thalassemia major (ie, homozygous beta thalassemia), the production of beta-globin chains is severely impaired, because both beta-globin genes are mutated. In beta thalassemia major, one of the beta-globin chains is impaired.

The severe anemia resulting from this disease, if untreated, can result in high-output cardiac failure, which causes the highest mortality. Iron overload which occurs relatively quickly due to recurrent transfusions, can be reduced with INTRAVENOUS desferrioxamine. The side effects are deafness and retinal damage. HAEMOLYTIC ANAEMIAS Hereditary spherocytosis gene for ankyrin (cell membrane protein) has been mapped to chromosome 8 and is autosomal dominant. The condition is commoner among Northern Europeans. It presents in childhood with jaundice and splenomegaly. Spherocytes on blood film suggests hereditary spherocytosis (HS). In HS the red cells are smaller, rounder, and more fragile than normal. The osmotic fragility test is the best diagnostic test, although AGLT (Acidified glycerol lysis test) may be used as a screening tool for relatives. Treatment is with splenectomy. Glucose 6 phosphate dehydrogenase deficiency (X linked recessive) is seen in African, Mediterranean, Iraqi, Jew and South East Asian Chinese people. It predisposes to a haemolytic anaemia reaction to drugs and infection. The blood film in G6PD deficiency shows characteristic blister cells, where the membrane protrudes out like a blister. Drugs causing haemolysis in G6PD deficiency are: Sulphonamides Antimalarials (chloroquine, quinine, primaquine) Antipyretics (aspirin + paracetamol) Chloramphenicol nitrofurantoin Dapsone Probenecid Vit K

OTHER ANAEMIAS A high MCV with normal folate and B12 levels, normal iron and a blood film showing anisocytosis and poikilocytosis suggests sideroblastic anaemia. Sideroblasts are abnormal red cell precursors with iron loaded mitochondria, forming a ring around the nucleus. In sideroblastic anaemia, there is increased bone marrow iron. This is reflected in the increased iron stores in ferritin and also haemosiderin and ringed premature red blood cells (sideroblasts) due to excess iron. Sideroblastic anaemia is associated with: ALA synthase 2 deficiency Alcohol Lead Myelodysplasia drugs (paracetamol, phenacetin, pyrazinamide and chloramphenicol). In sideroblastic anaemia, there is a defect in haem synthesis (failure to incorporate iron into the haemoglobin molecule). This leads to excess loading of iron to compensate in red cell precursors and into iron stores, sometimes causing haemosiderosis in the liver. Desferrioxamine therapy may help. Aplastic anaemia can be congenital (Fanconi's anaemia) or acquired due to drugs (benzene compounds, insecticides, gold or penicillamine). Pernicious anaemia (PA) is a disease of the stomach that is characterised by megaloblastic anaemia due to vitamin B12 deficiency. It is secondary to intrinsic factor deficiency and gastric atrophy. It usually has an autoimmune basis. Pernicious Anaemia primarily affects the elderly - most patients are over 60 years of age. Women are affected more often than men, in a ratio of 3:2. It may be associated with

autoimmune diseases, such as Addison's disease, hypothyroidism and also an increased risk of gastric carcinoma. CLOTTING DISORDERS Haemophilia A (factor VIII deficiency) or B (factor IX deficiency) both produce a prolonged APTT. They are both X-linked recessive. An isolated prolonged APTT will be caused by deficiencies in factors VIII, IX, XI and XII and by von Willebrands disease. Factor XII deficiency is not associated with increased bleeding. Von Willebrand's disease is autosomal dominant. Bleeding following trauma, epistaxis and menorrhagia are described. The tests to diagnose vWD include: bleeding time (prolonged) factor VIII level test (measures the level of factor VIII and its ability to function) von Willebrand factor antigen test (the disorder is considered mild if a person has 20% to 40% of the normal amount, severe if the amount is less than 10% of normal) ristocetin cofactor activity test (measures how well the von Willebrand factor is working) Therapy includes DDAVP , Factor VIII concentrates and plasma products, and Tranexemic acid (fibrinolytic inhibitor). Type I heparin induced thrombocytopenia (HIT) occurs within a few days of heparin and is usually mild. In this case, type II HIT is more likely, and this occurs slightly later (5-15 days). It is associated with thrombosis and a low platelet count. Alternative anticoagulation should be used (hirudin, danaparoid sodium). Side effects of heparin: Alopecia thrombocytopenia osteoprosis The main inherited thrombophilic defects are: Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V Leiden Prothrombin 20210 gene mutation PLATELET DISORDERS Disseminated intravascular coagulation is caused by inappropriate and excessive activation of the haemostatic systems. 60% are caused by Gram negative sepsis. Other causes include viral infections, metastatic carcinoma, leukaemia, obstetric causes, extensive trauma and burns.

APTT, PT and TT are all prolonged, platelets and fibrinogen are low, D-dimers/FDPs are high. Treatment is of underlying causes and by control of the haemorrhagic state. Platelets, blood, cryoprecipitate and fresh frozen plasma may all be required. Features consistent with a diagnosis of immune thrombocytopenic purpura (ITP) are thrombocytopenia with platelets being normal in size or may appear larger than normal, but uniformly giant platelets (approaching the size of red cells) should be absent. The morphology of red blood cells and white blood cells should be normal. In younger patients with ITP, the disease usually remits spontaneously within several weeks and no treatment is usually required unless there is significant bleeding. However, after adolescence, the disease tends to run a chronic relapsing course and therefore requires therapy. First line therapy is oral steroids. Patients who are refractory to, or are intolerant of steroids may respond to intravenous immunoglobulins (IVIg) or anti-D. Thrombotic thrombocytopenic purpura (TTP) is characterised by microangiopathic haemolysis and thrombocytopenia. There is a spectrum of presentations with TTP-HUS. Neurological features are present in 60% of patients of TTP and renal failure is often associated in HUS (haemolytic uraemic syndrome). With the introduction of plasma exchange (recommended treatment), the survival rate has improved from approximately 3% prior to the 1960s to 82%. MYELOPROLIFERATIVE DISORDERS In myelofibrosis, splenomegaly occurs with a fibrotic process. Leucoerythroblastic anaemia (red cell and white cell precursors) are seen on the blood film. Fibrous tissue infiltration of the bone makes it difficult to aspirate bone marrow. Bone pain, bleeding (platelet dysfunction) may occur. The criteria for Polycythaemia Rubra Vera are: 1) increased red cell mass 2) splenomegaly 3) increased platelets, leucocytes, INCREASED NAP score and B12 (increased B12 binding protein release). Increased serum viscosity may arise from hyperglobulinaemia or from an increased red cell mass, polycythaemia. Treatment of hyperviscosity syndrome should be with fluid replacement and venesection. The NAP score is a semiquantitative cytochemical assessment of alkaline phosphatase in neutrophils. The NAP score is based on staining intensity, with a possible score of 0-400. It differentiates chronic myeloid leukaemia (low) from reactive leucocytosis (high), eg bacterial infection. It may assist in the differentiation of polycythaemia rubra vera (high) from other causes of erythrocytosis (normal). LEUKAEMIAS AND LYMPHOMAS Acute leukaemia is defined as blast cells comprising 30%

Chronic lymphocytic leukaemia : high white cell count with predominant lymphocytosis and anaemia . Immunophenotyping can be used for classification of undifferentiated leukemia as lymphoid or myeloid and subclassification of leukemias. Chronic lymphatic leukaemia is characterised by a lymphocytosis. The blood film shows mature lymphocytes with smear or smudge cells (they are squashed cells). Gleevec (imatinib mesylate, Novartis), is an oral drug which interferes with the action of the abnormal Bcr-Abl tyrosine kinase in CML white blood cells. Before Gleevec, the most common drugs used to treat CML were the oral treatments hydroxyurea and busulphan. Acute Lymphoblastic Leukaemia : The bcr gene is found on chromosome 22 and abl gene on 9. This is known as the Philadelphia chromosome (named because it was discovered at hospital in Philadelphia). The Philadelphia chromosome is found in 25% of ALL patients (not AML). The philadelphia chromosome is associated with bad prognosis. Prognostic factors are more important in ALL than the other leukaemias. These are the prognostic factors: Age at diagnosis: Children younger than 1 year and children older than 10 years are considered high-risk patients. White blood cell (WBC) count: Children with ALL who have especially high WBC counts are classified as high risk Sex: Girls with ALL have a slightly higher chance of being cured than do boys. Organ Spread: Spread of the leukemia into the spinal fluid, or the testicles increases the chance of a poor outcome. Immunophenotype of the leukemia cells: Children with pre-B or early pre-B-cell ALL do better than those with T-cell or mature B-cell (Burkitt) leukemia. Number of chromosomes: Patients are more likely to be cured if their leukemia cells have an increased number of chromosomes (called hyperdiploidy). Children whose leukemia cells have fewer chromosomes than normal (hypodiploidy) have a less favorable outlook. Chromosome translocations: Children with a translocation between chromosomes 9 and 22 (the Philadelphia chromosome), 1 and 19, or 4 and 11 have a less favorable prognosis. Response to therapy: Children whose leukemia responds completely to therapy within 7 or 14 days of chemotherapy have a better outlook. The Retinoic acid receptor- RAR alpha gene maps to chromosome 17q21, close to the t(15;17), (q21-q11-22) translocation. A fusion of the promyelocytic gene (PML) with the RAR gene is specifically associated with acute promyelocytic leukaemia. In Acute Myeloid Leukaemia, 8:21 and 15:17 translocations are associated with better prognosis compared to 9:22 and deletions of chromosome 5 and 7. Auer rods are due to stacking of granules in myeloblasts (granulocytes). Promyelocytes and Auer rods are found in M3 (morphological classification of M1-M7).

M6 and M7 which are the most differentiated have the worst prognosis. In AML, the most common abnormality is DIC, which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products. Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC. Hairy cell leukemia is a B cell lymphoproliferative disorder in which monocytopenia occurs. Burkitt's lymphoma is a high grade B-cell NHL which is very sensitive to chemotherapy and radiotherapy (95% response rate). It is associated with Ebstein Barr virus infection. Abnormalities of c-myc are almost commonly seen in Burkitts lymphoma with about 75% of cases carrying t(8;14) and 20% carrying t(2;8) translocations. Hodgkin's lymphoma is rare in children aged less than 6. Common presenting features for Hodgkin's disease are Pel Ebstein fever, weight loss, alcohol induced pain and lymphadenopathy. Cold agglutinins can occur, leading to possible haemolytic anaemia. Histology demonstrates Reed-Sternberg cells, which are pathognomonic. Reed-Sternberg cells are characteristic bi-nucleate or multinucleate cells found in Hodgkins disease (owls eye nuclei or church plate nuclei). Nodular sclerosing is the commonest and lymphocyte depleted is the rarest form. The lymphocyte predominant form has the best prognosis, whilst the lymphocyte depleted form has the worst. Staging of Hodgkins lymphoma is via the Modified Ann Arbor classification: I Involvement of a single lymph node region or a single extralymphatic site or organ. II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or one or more lymph node regions plus an extralymphatic site (IIE). III - Involvement of lymph nodes on both sides of the diaphragm. IV - Involvement of one or more extralymphatic organs (Lung, liver, bone marrow, with or without lymph node involvement). MISCELLANEOUS DISORDERS Cold Agglutinins: IgM which agglutinate red cells between 0 and 4C. Causes are: coxsackie virus, EBV, CMV, Mumps, HIV, syphilis, malaria, legionella, mycoplasma, listeria, E coli, lymphoma, leukaemia, myeloma, Waldenstroms macroglobulinaemia, . Folate deficiency is treated by giving folic acid orally at 1 to 5 mg daily. B12 deficiency is usually treated by parenteral administration of B12. Therapeutic doses of folate will correct the hematologic abnormalities due to cobalamin deficiency also but the neurologic abnormalities can worsen, it is best to give B12 first or both B12 and folate but never folate alone.

Methaemoglobinaemia a cause of cyanosis because it causes the formation of reduced Hb >1.5 g/dl. It is due to oxidised iron from Fe2+ to Fe3+ in Hb and may cause precipitation as Heinz bodies. About forty substances have been implicated in causing this condition, the most prominent being dapsone, nitrates, prilocaine, antimalarials, sulphonamides and dyes. Standard pulse oximeters give spuriously low readings in the presence of excess methaemoglobin. Methylene blue is indicated in any patient with symptoms and/or signs of hypoxia (mental changes, tachycardia, dyspnoea, chest pain). Hypoxia, acidosis, high CO2, raised 2,3 DPG, raised temperature, high altitude and anaemia all shift the oxygen dissociation curve to the right, reducing haemoglobins affinity for oxygen. Raised levels of HbF (fetal hemoglobin) shifts the curve to the left. Myelodysplasia can be classified into five subtypes - Refractory anaemia Refractory anaemia with ring sideroblasts Refractory anaemia with excess blasts Refractory anaemia with excess blasts in transformation (near AML) CML. Myelodysplastic syndromes are associated with pancytopenias along with dyserythropoietic ringed sideroblasts and blast cells in the peripheral circulation. Few patients require aggressive therapy such as chemotherapy, it is reserved for younger patients to prevent progression to AML. Supportive therapy includes blood transfusions, platelet transfusions or G-CSF to improve blood counts. However median survival is only 2 years. In multiple myeloma, the bone marrow shows increased amounts of plasma cells (>30%). In multiple myeloma there is raised protein (60-80 normal range). This paraproteinaemia is due to IgG proliferation. There is also low white cell count due to bone marrow infiltration, hypercalcaemia and renal failure. Waldenstroms macroglobulinaemia is a type of non-Hodgkins lymphoma. It is a condition which typically presents in the seventh and eighth decade of life. Hepatosplenomegaly occurs. Increased serum proteins leads to a variety of symptoms: Neuropathy Headache and focal nervous system impairment congestive cardiac failure. It is characterized by the presence of a high level of a macroglobulin immunoglobulin M [IgM note that myeloma is IgG] and elevated serum viscosity in the presence of a

lymphoplasmacytic infiltrate in the bone marrow. The treatment is chemotherapy (Chlorambucil or Fludarabine) Marble bone disease is due to a defect in osteoclast function, causing extensive mineralisation of bone and reduction in bone marrow space. Primary thrombocytosis can be caused by: Essential thrombocytosis Chronic myeloid leukaemia Polycythaemia vera Myelofibrosis Myelodysplastic syndromes Following splenectomy, patients should receive lifelong penicillin prophylaxis. The major complication of splenectomy is overwhelming sepsis with encapsulated bacteria (eg, S pneumoniae, H influenzae, N meningitidis). The overall risk of sepsis in asplenic patients is approximately 2% but varies depending on the age and underlying diseases. Paroxysmal nocturnal haemoglobinuria (PNH) is an aplastic anaemia like syndrome which red cells are predisposed to complement lysis and resultant haemolytic anaemia. There is a pancytopenia as well as a tendency towards Budd Chiari thrombosis. The diagnostic test is the HAM test. Serum (which contains complements) is acidified (activates the complement pathway) and mixed with red cells which undergo lysis. Haemosiderin is a by product of haem breakdown containing iron. Excess amounts leads to renal damage, and is also lost in the urine. In PNH, there is a loss of anchor protein (GPI glycosylphosphatidyl inositol) which hold different antigens e.g. CD59, CD14. These are regulatory proteins for the complement pathway. Tumours and virus associations: Burkitt's lymphoma - Ebstein Barr virus Kaposi's sarcoma - Herpes virus and HIV adult T cell leukaemia - HTLV cervical carcinoma HPV In the UK every blood donation is tested for evidence of hepatitis B, hepatitis C, HIV-1, HIV-2 and syphilis. However, although there are recent concerns regarding tranmission of new variant CJD, there are no reliable screening methods yet.

Compiled by Ahmed HAKEM ahmedhakim_227@yahoo.com http://ahmedhakim.125mb.com